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Halo and Pseudohalo Gold(I)–NHC Complexes Derived from 4,5-Diarylimidazoles with Excellent In Vitro and In Vivo Anticancer Activities Against HCC

  • Mianli Bian
    Mianli Bian
    Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
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    • , 
  • Rong Fan
    Rong Fan
    Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
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    • , 
  • Guizhi Jiang
    Guizhi Jiang
    Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
    More by Guizhi Jiang
    • , 
  • Yingxiang Wang
    Yingxiang Wang
    Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
    More by Yingxiang Wang
    • , 
  • Yunlong Lu
    Yunlong Lu
    Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
    More by Yunlong Lu
    • , and 
  • Wukun Liu*
    Wukun Liu
    Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
    State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China
    State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210023, P. R. China
    *Email: [email protected] and [email protected]. Tel: +86-25-85811633.
    More by Wukun Liu
    Orcidhttp://orcid.org/0000-0002-0469-907X
Cite this: J. Med. Chem. 2020, 63, 17, 9197–9211
Publication Date (Web):August 3, 2020
https://doi.org/10.1021/acs.jmedchem.0c00257
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Abstract

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A series of halo and pseudohalo gold(I)–NHC complexes (NHC–Au–X) (X = Cl, Br, I, NCO, and OAc) derived from 4,5-diarylimidazoles were synthesized, structurally characterized, and analyzed for their biological activities. The most active complex was iodo(1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene)gold(I) (6), which was at least 2-fold more cytotoxic than cisplatin and auranofin against hepatocellular carcinoma (HCC) cells. In vivo studies indicated that complex 6 exhibited a considerably higher anticancer efficacy (IRT = 75.7%) than cisplatin (IRT = 44.4%) in a HepG2 xenograft mouse model and ameliorated liver injury caused by CCl4 in chronic HCC. Further studies revealed that complex 6 can inhibit the expression of the thioredoxin reductase (TrxR) both in vitro and in vivo, block the HepG2 cells in the G2/M phase, induce reactive oxygen species (ROS) production, damage mitochondrial membrane potential (MMP), and promote HepG2 cell apoptosis.

1. Introduction

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Hepatocellular carcinoma (HCC), as the main malignant tumor, is recognized as the fifth most diagnosed and the second most fatal disease in the world. (1) It begins at hepatocytes and is the most common subtype of primary HCC cells. (2) Recently, the most effective treatments for HCC are surgery and liver transplantation. Even though great progress has been made in classic anti-HCC treatments, there are still many restrictions in searching for reasonable therapeutics and preventing a poor prognosis. (3,4) Hence, identifying the most effective anti-HCC treatments remain a nascent area.
Gold complexes have recently obtained increased attention because of their high anticancer activities against cancer cells, including HCC. Most of them displayed a lower toxicity, lower resistance factors, and a higher antiproliferative activity than those of platinum-based drugs. (5−9) Among gold anticancer pharmaceuticals, auranofin (an antirheumatic drug) has been or still is under clinical trials for the treatment of cancers, such as lung cancer (NCT01737502), ovarian cancer (NCT01747798), and chronic lymphocytic leukemia (NCT01419691). (6,10−12) Interestingly, recent studies reported that auranofin could inhibit HCC cell growth in vitro and suppress the growth of HCC tumors in vivo through inhibiting thioredoxin reductase (TrxR) activity. (13) Auranofin has a high potency to bind with selenocysteine residues in TrxR, owing to the formation of an irreversible and stable adduct. (8,9) TrxR is a selenoenzyme and plays an important role in redox homeostasis. (14) It can aggravate HCC growth and has been recognized as a prognostic marker and a hopeful survival indicator in HCC. (13,15−17) Thus, TrxR is a promising target and is highly demanded for HCC treatment.
However, gold complexes (e.g., auranofin) are easily metabolized by thiol-containing biomolecules, and the coordinated ligands are mostly lost before reaching the target enzyme. (5,7,8) Continuous reports have shown that sulfur-containing amino acids such as cysteine and methionine easily react with gold complexes, so the significant side effects are the generation of metal-protein adducts and resulting in nephrotoxicity. (7,9,18−21) The strong metabolization of gold complexes has limited the reasonable design of metallodrugs. Thus, the development of higher-stability gold complexes and changing their ligands have drawn wide attention.
N-Heterocyclic carbenes (NHCs) offer obvious advantages, among which are the high stability of organometallic complexes and excellent biological potentials. Many studies have confirmed that NHC carrier ligands of metal complexes, such as gold–NHC complexes, have great cytotoxic effects, showing highly modular scaffolds that are particularly adaptable to drug design. (22−29) It is relatively easy to modify the NHC substituents because the ligand backbone groups can be systematically varied, leading to complexes with differing lipophilicities or sterics.
Recently, a series of monogold(I/III)–NHC complexes derived from 4,5-diarylimidazole with effective anticancer activities were published. (22) Initial structure–activity relationship (SAR) studies demonstrated that 4-methoxy- and 4-fluoro-substituted diaryl gold(I)–NHC complexes were the most active complexes among other gold–NHC complexes. No increase in the anticancer potential was observed by oxidating the gold(I) to gold(III), exchanging the N-ethyl substituent, or changing the para position of the substituted group to the ortho or meta positions in the aromatic ring.
In the continuation of studies of this kind on monogold–NHC complexes derived from 4,5-diarylimidazole, here we report the synthesis and structural characterization of a series of halo and pseudohalo gold(I)–NHC complexes (NHC–Au–X) (X = Cl, Br, I, NCO, and OAc). We evaluated their anti-HCC activity both in vitro and in vivo and further investigated the application of an effective agent to uncover a mechanism of thioredoxin system inhibition.

2. Results and Discussion

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2.1. Synthesis and Characterization

The synthetic routes to halo and pseudohalo gold(I)–NHC complexes 1–10 are outlined in Scheme 1. 4-Methoxy- and 4-fluoro-substituted diarylimidazolium salts a and b were prepared according to our previously published methods. (23) The chloro–gold(I)–NHC complexes (1 and 2) were synthesized according to a previously described procedure starting from imidazolium salts a and b. They were obtained by treating imidazolium salts a and b with silver oxide in CH2Cl2 to form an intermediate Ag(I)–NHC complex, followed by a ligand exchange reaction with Me2SAuCl. (22,30,31) The bromo–gold(I)–NHC complexes (3 and 4) and iodo–gold(I)–NHC complexes (5 and 6) were synthesized by treating the chloride with the corresponding sodium salts; for the synthesis of cyanato–gold(I)–NHC complexes (7 and 8) and acetato–gold(I)–NHC complexes (9 and 10), the exchange of the chloride was mediated by the appropriate silver salts. The target complexes were fully characterized by NMR spectroscopy and mass spectrometry, and their purities were tested by elemental analysis and HPLC analysis. The 1H NMR spectra of gold complexes 1–8 are very similar and not suitable to determine their differences. However, the chemical shift of the gold-bound carbene (NCN–Au) carbon varied widely with differing halides and pseudohalides from δ 161.52 to δ 180.28 ppm in the 13C NMR spectrum (Table 1).

Scheme 1

Scheme 1. Synthesis of Gold(I)–NHC Complexes
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Table 1. 13C NMR Chemical Shift of the Au–Ccarbene Carbon
compoundδ (ppm)compoundδ (ppm)
1169.686179.24
2168.497167.70
3173.278166.54
4172.079164.16
5180.2810161.52

2.2. The X-ray Crystal Analysis

To evaluate the structure of the gold(I)–NHC complexes, complex 6 was crystallized from a CH2Cl2/n-hexane solution, and the structure was determined by X-ray diffraction (Figure 1 and Tables S1–S6). The molecular structure of the iodo–gold(I)–NHC complex 6 is a linear monocarbene gold complex with common Au–Ccarbene and Au–I bond lengths of 1.998(3) and 2.5524(3) Å, respectively. The C1–Au1–I1 bond was almost linear with an angle of 177.99(8)°.

Figure 1

Figure 1. Crystal structure of the iodo–gold(I)–NHC complex 6.

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2.3. Stability Study

Initially, the stability of complex 6 in acetone-d6 was tested over five days by examining the 1H NMR spectra of complex 6 (Figure S1). The 1H NMR spectra of complex 6 did not change significantly within five days, indicating that complex 6 was very stable in the acetone-d6 solution. Then, the stability of complex 6 in a mixed solution (D2O/acetone-d6 = 1:9) was measured over time by examining the 1H NMR spectra of complex 6 (Figure S2). The signals of complex 6 were stable in deuteroxide-containing acetone-d6 solution over 4 days. Besides, we also tested the stability of complexes 2, 4, and 6 in a phosphate buffer solution (PBS) (pH 7.28), which contained a 100× higher concentration of GSH than that of complexes 2, 4, and 6 by UV–vis spectrophotometry. As shown in Figure S3, complexes 2, 4, and 6 were relatively stable in the PBS buffer with a high concentration of GSH. The stability of complex 6 was consistent with that of the chloro–gold(I)–NHC complex (32) and iodo(triethylphosphine)gold(I) complex. (11,33) However, it should be mentioned that some chloro–gold(I)–NHC complexes might rearrange to gold(I)–bisNHC complexes in solutions (30,34) and that iodo–gold(I)–NHC complexes might be susceptible to oxidation. (31)

2.4. In Vitro Antiproliferative Activity

As gold complexes displayed potential anti-HCC activity, (13) we first used the MTT assay to detect the antiproliferative activity of gold–NHC complexes 1–10 in HepG2, SMMC-7721, and Hep3B cancer cells. Auranofin and cisplatin were used as positive controls. As showed in Table 2, both cisplatin (HepG2, IC50 = 1.35 μM; SMMC-7721, IC50 = 3.54 μM; and Hep3B, IC50 = 1.15 μM) and auranofin (HepG2, IC50 = 1.74 μM; SMMC-7721, IC50 = 2.24 μM; and Hep3B, IC50 = 1.93 μM) were potently cytotoxic against HCC cells in the micromolar range. Among halo and pseudohalo gold(I)–NHC complexes, iodo–gold(I)–NHC complexes (5 and 6) and acetato–gold(I)–NHC complexes (9 and 10) displayed superior or comparable anti-HCC activities compared with those of cisplatin and auranofin. In particular, the most active iodo–gold(I)–NHC complex 6 (HepG2, IC50 = 0.50 μM; SMMC-7721, IC50 = 0.92 μM; and Hep3B, IC50 = 0.52 μM) was at least 2-fold more cytotoxic than both cisplatin and auranofin against HCC cells.
Table 2. Antiproliferative Effects Against HepG2, SMMC-7721, and Hep3B Cells After 72 h of Incubationa
compoundHepG2SMMC-7721Hep3B
cisplatin1.35 ± 0.123.54 ± 0.281.15 ± 0.11
auranofin1.74 ± 0.322.24 ± 0.241.93 ± 0.21
1>2016.14 ± 2.79>20
215.50 ± 1.217.70 ± 0.417.90 ± 0.89
33.72 ± 0.159.41 ± 0.714.95 ± 0.11
44.44 ± 0.3210.15 ± 1.294.71 ± 0.22
51.08 ± 0.121.88 ± 0.151.05 ± 0.10
60.50 ± 0.020.92 ± 0.080.52 ± 0.04
712.10 ± 1.828.76 ± 0.827.86 ± 1.22
83.12 ± 0.163.83 ± 0.182.41 ± 0.31
91.22 ± 0.112.47 ± 0.241.21 ± 0.11
100.71 ± 0.051.07 ± 0.090.77 ± 0.08
a

IC50 values are the mean ± SD (μM).

For the halo gold(I)–NHC complexes, the size of the halogens has a large effect on the cytotoxicity of the gold complexes; a larger halogen size (I > Br > Cl) leads to a higher antiproliferative activity against HCC cells (5 (I) > 3 (Br) > 1 (Cl) and 6 (I) > 4 (Br)> 2 (Cl)). These findings indicated that replacing the chloride (1 and 2) or bromide (3 and 4) ligand with iodide (5 and 6) may increase their lipophilicity, thus enhancing the drug bioavailability. For the pseudohalo gold(I)–NHC complexes, acetato–gold(I)–NHC complexes (9 and 10) were 3-fold more active than the corresponding cyanato–gold(I)–NHC complexes (7 and 8) against HCC cells. In addition, we used an XTT assay to test the cytotoxicity and calculate the IC50 values of the complexes as a parallel verification (Figure S4). (35) Interestingly, we observed that the results are similar to the data from the MTT assay.
The principle of the LDH assay to test the cytotoxicity is completely different from those of MTT and XTT assays. (36) LDH release is considered an important indicator of the cell membrane integrity and is extensively applied to cytotoxicity testing. Thus, we detected the LDH leakage after treatment with the complexes to cause plasma membrane disintegration. LDH release was obviously caused with the treatment of complexes 5, 6, 9, and 10 (Figure S5), indicating that heavy injury and cytotoxicity to the cell membrane integrity were detected in HCC cells.
We also tested the cytotoxicity of the complexes in two different normal cells, human normal hepatocytes (LO2) and cervical epithelial (H8) cells, using the MTT assay. Interestingly, the most active complex 6 showed some degree of selectivity for HCC cells (HepG2, IC50 = 0.50 μM; SMMC-7721, IC50 = 0.92 μM; and Hep3B, IC50 = 0.52 μM), as it was less cytotoxic against normal cells (LO2, IC50 = 1.35 μM and H8, IC50 = 1.29 μM). Other complexes (5, 9, and 10) displayed a slight selectivity for cancer cells. Cisplatin and auranofin were less selective for HCC cells and showed similar activities against the normal cells. In addition, similar phenomena were observed in the XTT and LDH assays (Figures S6–S8).
Next, we chose reasonable doses that can injure the cancer cells but have no toxic effect on normal cells. In Figure S9, we can see that doses of 0.5, 1, and 2 μM of complex 6 could injure the HepG2 cells but have no toxic effects on LO2 cells. The doses of complex 6 caused minimally harmful effect to normal cells and did not show a significant difference in 24 h of treatment. In other words, these doses and complex action time are safe in cell samples.

2.5. TrxR Inhibition

TrxR is considered to be a significant target for gold complexes and is often overexpressed in HCC cells. (7,37) Thus, we tested the TrxR inhibitory activity of the most active complex 6 in both an isolated enzyme and HepG2 cells. As demonstrated in Figure 2A, the purified TrxR activity was substantially and dose-dependently inhibited by complex 6, with an IC50 value of 2.14 μM. Then, we explored the TrxR inhibitory effect of complex 6 in HepG2 cells. Different concentrations of complex 6 were treated with HepG2 cells for 48 and 72 h, and TrxR assay kits were used to detect the TrxR activity. We found that complex 6 showed a TrxR inhibitory activity (IC50 = 2.77 μM) in 72 h of treatment (Figure 2B).

Figure 2

Figure 2. Complex 6 inhibited the TrxR expression. (A) Inhibition to the activity of purified TrxR by complex 6. (B) In HepG2 cells after treatment with complex 6 for 48 and 72 h. (C) mRNA levels of TrxR. (D) Immunofluorescence analysis (original magnification is 40×). (E and F) Western blot analysis. Error bars are the SD, n = 3. Statistical significance of differences in mean values are *p < 0.05, **p < 0.01, and ***p < 0.001. Scale bars are 25 μm.

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The TrxR inhibition by complex 6 in both an isolated enzyme and cells was similar to those of the reported metal-containing and natural TrxR inhibitors. (38−40) Because of the different coordination numbers, relative stabilities, and modes of structure, (41) the enzyme inhibitory activity from complex 6 was lower than that of auranofin in our previous report (IC50 = 82.6 nM). (42) However, it should be noted that the gold complex auranofin showed a rapid metabolization due to the conjugation to serum proteins before reaching the main target enzyme. (5−8,20)
To further evaluate the TrxR inhibition efficiency, we identified the influence of complex 6 on intracellular mRNA levels of TrxR. Real-time PCR indicated that complex 6 reduced the mRNA level in a dose-dependent manner (Figure 2C). Immunofluorescence analysis and a Western blot assay further confirmed these results (Figure 2D–F). The level of TrxR was upregulated in HepG2 cells and was decreased by complex 6 dose-dependently. Consequently, these data confirmed that complex 6 has a certain TrxR inhibitory activity in vitro and that TrxR may indeed be one of the main targets for this iodo–gold(I)–NHC complex.

2.6. ROS Production and Mitochondrial Dysfunction

TrxR is an important antioxidant regulator in mitochondrial dysfunction, and mitochondrial injury causes the increase of ROS. (38,43) To state this result clearly, we tested the ROS expression in HepG2 cells after complex 6 treatment for 12 h. DCFH-DA is a recognized probe and shows the burst of ROS after treatment with complex 6 (2 μM) (Figure 3A). In addition, we discussed another dye, dihydroethidium (DHE), to confirm the generation of intracellular ROS. (44) DHE can penetrate plasma membrane and intercept ROS, especially the superoxides. The ROS probe oxidizes into a red fluorescent substance in the presence of active oxygen. The red fluorescent intensity is directly proportional to the level of active oxygen in the cells. The results indicated that complex 6 could greatly trigger ROS generation (Figure 3B).

Figure 3

Figure 3. Complex 6 induced ROS production and mitochondrial dysfunction. (A and B) Bright field image and ROS positive cells after treatment with complex 6 by DCFH-DA and DHE assays (original magnification is 20×), respectively. (C) Mitochondrial membrane damage imaged by JC-1 staining (original magnification is 40×). Scale bars are 25 μm.

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To verify whether the complex had an intrinsic luminescence that would interfere with the results of apoptosis and ROS assays, we performed fluorescence assays of complex 6. As shown in Figure S10, there were no emission signals from 545 to 700 nm at a concentration of either 2 or 20 μM of complex 6, while the maximum excitation wavelength of the ROS probe was 610 nm. Thus, complex 6 has no intrinsic luminescence that would interfere with the results of the apoptosis and ROS assays.
Additionally, we considered and detected other proteins related to ROS to describe the detailed mechanism of ROS more clearly. Pin1 can subject Ser/Thr–Pro phosphorylated proteins to postphosphorylation prolyl isomerization, which in turn can regulate the cell cycle and apoptosis. (45) The results by a Western blot assay indicated that complex 6 could inhibit Pin1 expression (Figure S11A and B). The NEDD8-activating enzyme (NAE) is significant among the NEDD8 conjugation pathway, which can adjust the degradation of related proteins. (46) NEDD8 is involved in important biological processes, such as cell proliferation, DNA damage repair, protein stability, transcription regulation, and chromosome formation. We found that complex 6 could obviously inhibit the NEDD8 level (Figure S11A and B). Accumulating evidence indicated that MAPKs, including ERK1/2, JNK1/2, and p38, play a critical role in intracellular ROS levels. (47−49) Here, the phosphorylation levels of those MAPK proteins were evaluated after 24 h of treatment with complex 6. The levels of p-ERK1/2/ERK1/2, p-JNK1/2/JNK1/2, and p-p38/p38 increased in a concentration-dependent manner (Figure S11C and D). These results further demonstrate an enhancement of the intracellular ROS production after treatment with complex 6.
In addition, it was reported that gold complexes could trigger antimitochondrial and apoptotic effects via inhibiting the activity of TrxR. (37) We tested the mitochondrial membrane potential (MMP) level using a JC-1 kit and observed that the green (monomeric) fluorescence increased in the complex 6 treatment group compared to the control (DMF) (Figure 3C). This result showed that the mitochondrial dysfunction may be critical in cell death processing induced by complex 6. Furthermore, as MMP is necessary to ATP generation, we treated HepG2 cells with complex 6 at different concentrations to verify whether complex 6 would affect ATP. Results demonstrated that the complex 6 treatment displayed a dramatically lower ATP activity than that of the DMF control (Figure S12), indicating that complex 6 could inhibit ATP release. Thus, these data demonstrated that complex 6 could impair mitochondrial function effectively in HepG2 cells and that mitochondrial dysfunction was involved in the cytotoxicity of complex 6.

2.7. Apoptotic Pathways and Cell Cycle Analysis

ROS generation could lead to mitochondrial disorder and finally result in cell apoptosis. (50−52) After treatment with complex 6 (0.5, 1, and 2 μM) for 72 h, the apoptotic cells increased in a dose-dependent manner (Figure 4A and B). Bcl-2 can adjust the mitochondrial membrane permeabilization, and it plays a vital role in programmed cell apoptosis. To demonstrate the induction of the intrinsic pathway, we detected some important protein levels using Western blot assays. Complex 6 increased the expression of pro-apoptosis proteins (Bax, AIF, cytochrome c, and cleaved-PARP/PARP) but reduced the expression of the anti-apoptosis protein Bcl-2 (Figure 4C–F). The marker of the apoptotic factor (AIF) was tested by an immunofluorescence assay, and the result is consistent with that of the Western blot assay (Figure S13). In light of the morphological characteristics in apoptotic cells, we used Hoechst 33258 staining assays to induce the nuclear morphology with the complex 6 treatment. The cells without the complex 6 treatment demonstrated a weak blue fluorescence, appeared as regular round shapes, and also appeared brightly stained by the treatment of complex 6 (Figure S14).

Figure 4

Figure 4. Complex 6 induced HepG2 cells apoptosis. (A and B) Apoptotic cells after treatment with complex 6 for 72 h. (C–F) Western blot analysis of apoptosis factors after treatment with complex 6 for 24 h. Error bars are the SD, n = 3. Statistical significance of differences in mean values are *p < 0.05, **p < 0.01, and ***p < 0.001.

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Next, the effect of complex 6 on cell cycle progression was detected by PI (propidium diiodide) staining. HepG2 cells were treated with complex 6 (0.5, 1, and 2 μM) for 72 h. The result indicated that the cells obviously accumulated in the G2/M phase (Figure 5A and B). Based on this, we further detected the cycle-related protein levels in the G2/M phase, and the results showed that cyclin A and CDK2 expressions were reduced in a dose-dependent manner (Figure 5C and D). Taken together, these data clearly indicated that complex 6 could induce apoptosis and cell cycle arrest in HepG2 cells.

Figure 5

Figure 5. Cell cycle analysis. (A and B) Effects of complex 6 on cell cycle progression. (C and D) Western blot analysis. Error bars are the SD, n = 3. Statistical significance of differences in mean values are *p < 0.05, **p < 0.01, and ***p < 0.001.

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2.8. Activating ROS is Required for Complex 6 to Depress TrxR Expression

To explore the importance of ROS-induced apoptosis for complex 6 in HepG2 cells, we used the ROS-specific scavenger N-acetylcysteine (NAC) (2 mM) to inhibit the ROS expression. The immunofluorescence result showed that complex 6 inhibited the TrxR level; however, treatment with NAC distinctly counteracted this effect (Figure 6A). Western blot assays were consistent with the results (Figure 6B and C). Interestingly, complex 6 obviously decreased the HepG2 cell viability (Figure S15), which was partially or completely reversed by treatment with different concentrations of NAC (0.5–4 mM). These results strongly suggested both that complex 6 could activate ROS-induced apoptosis and that the biological action of complex 6 in HepG2 cells was reliant on its interaction with ROS.

Figure 6

Figure 6. The activation of ROS is required for complex 6 to inhibit TrxR expression and induce HepG2 cell apoptosis. (A) Immunofluorescence analysis of TrxR in HepG2 cells treated with complex 6 and NAC at 37 °C for 24 h (original magnification is 40 × ). (B and C) Western blot assays. (D) Immunofluorescence analysis (original magnification is 40×). (E and F) Western blot analysis. Error bars are the SD, n = 3. Statistical significance of differences in mean values are *p < 0.05 and ***p < 0.001. Scale bars are 25 μm.

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AIF has both apoptosis-inducing and oxidoreductase activity. Next, the apoptotic marker (AIF) expression was tested by immunofluorescence analysis, and the result showed that the complex 6 (1 μM) treatment dramatically increased the level of AIF (Figure 6D). In addition, the result of the Western blot assay was consistent with the immunofluorescence analysis (Figure 6E and F). Collectively, these findings revealed that complex 6 could restrain the expression of TrxR and promote HepG2 cells apoptosis as well as the fact that this phenomenon can be counteracted by the NAC treatment.
During aerobic metabolism, cells perform aerobic respiration in the mitochondria. Active oxygen is a series of intermediate products of molecular oxygen in the reduction process, which can attack living macromolecular substances and cause various damages to the body. We confirmed that the complexes have significant anti-HCC cell proliferation activity under normoxic conditions. To confirm the important role of ROS in the mechanism of antiproliferative activity, we further tested the cell activity under hypoxic conditions (1% O2, 5% CO2, and 94% N2 at 37 °C) for 72 h. The results using MTT, XTT, and LDH assays under hypoxic and normoxic conditions showed that our complexes had a similar inhibitory effect on tumor cell growth (Figures S16–S18). These results also fully indicated that complex 6 could inhibit the ability of TrxR to produce extensive ROS expression and finally lead to HepG2 cell apoptosis in hypoxic conditions.

2.9. In Vivo Antitumor Efficacy

To explore the in vivo impact of complex 6 against HCC, a subcutaneous xenograft model of HepG2 cells in nude mice was used. When the tumor volume reached 180–200 mm3, these mice were randomly divided into the following three groups (n = 4): the model group, the cisplatin-treated (5 mg/kg) group, and the complex 6-treated (5 mg/kg) group. Intraperitoneal administration of complex 6 for 15 days obviously reduced the HepG2 tumor volume and tumor weight vs the model and cisplatin treatment groups (Figure 7A and C). The complex 6 treatment group was well tolerated and without clear weight loss compared to the model and cisplatin treatment groups (Figure 7B). In addition, the complex 6-treated group showed an inhibition rate of tumor growth (IRT) as high as 75.7%, significantly higher than those of cisplatin (IRT = 44.4%) (Figure 7C and D) and the rhodium(I)–NHC complex (IRT = 45%, 10 mg/kg) with a similar scaffold. (50) The tumor nucleus in the model group was heteromorphic, displaying focal necrosis, pathological mitosis, and many new vessels in the tumor tissues. This phenomenon was alleviated by the complex 6 treatment, showing better effects than cisplatin treatment at the same dose (Figure 7F). In addition, H&E staining analysis of the complex 6-treated group further showed its nontoxicity in mouse hearts, livers, spleens, lungs, and kidneys compared with the model group and the cisplatin-treated group (Figure 7E). Thus, we can conclude that complex 6 can remarkably inhibit HCC tumor growth while simultaneously not damaging the hepatocellular morphology and increasing necrotic hepatocytes.

Figure 7

Figure 7. Complex 6 inhibited HepG2 xenograft tumor growth in nude mice. (A) The tumor volume of HepG2 xenografts in nude mice. (B) Body weight of the mice. (C) Tumor weights in nude mice. (D) Images of the representative tumors. (E and F) H&E staining of the major organs and tumor tissues (original magnification is 20×). For the statistics of each panel in this figure, data are expressed as the mean ± SD (n = 4); ###p < 0.001 compared with the model and ***p < 0.001 compared with cisplatin.

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Furthermore, TrxR levels in tumor tissues were measured by the immunohistochemistry and TrxR kit assays. Results indicated that the complex 6 treatment group obviously reduced the TrxR activity compared to the cisplatin treatment group (Figure 8A and C). Immunofluorescence and Western blot analyses of the three groups were consistent with the immunohistochemistry assay results (Figure 8B and D). In addition, we detected the expression of the apoptosis marker AIF; the results indicated that the complex 6-treated group could increase the levels of AIF compared to the model group and the cisplatin-treated group, indicating that complex 6 induced apoptosis in tumor tissues (Figure 8E–G). Taken together, treatment with complex 6 could inhibit the tumor growth in vivo by depressing the TrxR expression and have a better effect than the treatment with cisplatin.

Figure 8

Figure 8. Complex 6 reduced TrxR activity in tumor tissues. (A and E) The expression of TrxR and AIF, respectively in tumor tissues using immunohistochemistry assays (original magnification is 20×). (B and F) Immunofluorescence assays; DAPI was used to stain the nucleus (original magnification is 40 × ). The scale bar is 100 μm. (C) TrxR activity in tumor tissues using the TrxR activity detection kit. (C, D, G, and H) Western blot assays in tumor tissue lysates. β-Actin was used as a protein loading control. For the statistics of each panel in this figure, data are expressed as the mean ± SD, n = 4; #p < 0.05, ##p < 0.01, and ###p < 0.001 compared with the model and *p < 0.05 and ***p < 0.001 compared with cisplatin.

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2.10. Complex 6 Ameliorates Liver Injury and the Tumor Microenvironment InVivo

The animal models of HCC have supplied related information about the pathogenesis and molecular mechanisms. (4,50,53) Intraperitoneal injection of carbon tetrachloride (CCl4) is a very mature method to cause liver injury. (54) To further assess the in vivo anticancer activities of complex 6 against HCC, we chose continuous intraperitoneal injection of CCl4 (5 mL/kg) into the ICR mice for 16 weeks and then treatment with complex 6 (5 mg/kg) and a positive control (cisplatin, 5 mg/kg) to study the therapeutic potential of complex 6 in regard to liver damage.
All mice livers treated with CCl4 displayed cirrhotic features with rough and darkened surfaces (Figure 9A). H&E staining analysis indicated that the complex 6 treatment group (5 mg/kg) had remarkably improved morphological changes compared to those of the cisplatin treatment group (5 mg/kg) and CCl4 model group (Figure 9B). The generation of collagen accompanies fibrogenesis; therefore, we used Masson staining and Sirius red staining to test and verify the collagen accumulation. The results indicated that the collagen was significantly increased in the CCl4-injured liver; interestingly, it was obviously decreased in the complex 6 treatment group (Figure 9C and D). In addition, the levels of the liver injury markers (alanine aminotransferase (ALT), aspartate aminotransferase (AST), and LDH) were effectively reversed in the complex 6 treatment group (Figure 9E–G). Based on the results of the liver injury, ELASA analyses further confirmed that the level of TrxR in serum was high in the CCl4-injured liver, which is consistent with the report that the TrxR levels in serum were recently identified as possible prognostic markers for HCC. (17) As expected, treatment with complex 6 dramatically reversed these changes (Figure 9H). In general, these data powerfully demonstrated that treatment with complex 6, which showed better activity in these assays than treatment with cisplatin, did decrease the collagen accumulation and improve the liver injury in HCC model mice.

Figure 9

Figure 9. Complex 6 reduced the accumulation of collagen and ameliorated the damage of liver tissues in vivo. (A) The liver morphological changes. (B) H&E staining in liver tissues. (C and D) Masson and Sirius red staining. (E–H) Determination of serum ALT, AST, LDH, and TrxR levels, respectively. The original magnification is20×. For the statistics of each panel in this figure, data are expressed as the mean ± SD, n = 5; ###p < 0.001 compared with the control and *p < 0.05, **p < 0.01, and ***p < 0.001 compared with the CCl4 group.

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Chronic liver injury is usually accompanied by the generation of inflammation. (55) Inflammatory cells and regulatory factors exist in most liver injury microenvironments. (56) Inflammation is involved in tumor angiogenesis and tumor cell growth. Besides, the angiogenesis is first triggered by the inflammatory factor interleukin-1β (IL-1β). (57) As the results showed, serious inflammatory cell infiltration in CCl4 model livers was depressed after the complex 6 treatment, as characterized by a decrease in the number of tumor necrosis factor (TNF-α) and IL-1β using immunohistochemistry and immunofluorescence analyses (Figure 10A–D). It should be noted that cisplatin was slightly less active than complex 6 against HCC in these assays. In short, these results also indicated that treatment with complex 6 could ameliorate the CCl4-induced liver injury in vivo by reducing the TrxR expression and inflammation level.

Figure 10

Figure 10. Complex 6 ameliorated the inflammatory reaction to relieve liver injury. (A and C) Liver tissues were stained with immunofluorescence using antibodies against TNF-α and IL-1β. DAPI was used to stain the nucleus. The original magnification is 40 ×. (B and D) Immunohistochemistry staining. The original magnification is 20 ×.

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3. Conclusions

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A series of halo and pseudohalo gold(I)–NHC complexes were prepared, structurally characterized, and biologically investigated. A preliminary SAR study demonstrated that iodo–gold(I)–NHC complex 6 represented an effective cytostatic with cytotoxic effects against HCC (HepG2, SMMC-7721, and Hep3B) cells up to 3-fold higher than cisplatin or auranofin. This complex could inhibit the expression of TrxR, block HepG2 cells in the G2/M phase, induce the accumulation of ROS, damage the MMP, and promote HepG2 cell apoptosis.
In vivo studies demonstrated that complex 6 obviously decreased tumor growth and had a controllable toxicity. It repressed collagen accumulation and improved the liver injury in a chronic HCC model. Further studies also confirmed that this complex could inhibit HepG2 xenograft tumor growth in nude mice and ameliorate liver injury by inhibiting TrxR expression and the inflammation level, showing better effects than those of cisplatin. Overall, these in vitro and in vivo results suggest that complex 6 may significantly induce HCC cell death through enhanced oxidative stress and can be considered as a promising potential therapeutic candidate for the treatment of HCC.

4. Experimental Section

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4.1. Materials and Methods

The materials for synthesis were purchased from Energy Chemical and used without further purification. All deuterated solvents were bought from Cambridge Isotope Lab, Inc. (CIL). Antibodies, such as cleaved-PARP, BAK and cytochrome c for Western blot, were purchased from Abcam. p-ERK, p-JNK, and p-p38 were purchased from Affinity Biosciences. ERK, JNK, and p38 were purchased from Wanlei Bio. Pin1 and NEDD8 were acquired from Proteintech. The JC-1 kit, the ROS assay kit, and the ATP assay kit were purchased from Beyotime Biotechnology. Purified rat liver TrxR was purchased from Sigma Aldrich. The TrxR activity detection kit was bought from Solarbio. The purities of the newly synthesized gold–NHC complexes (>95%) were verified by elemental analyses and HPLC analysis (Figure S20).
1H NMR and 13C NMR spectra were recorded on a Bruker Avance III HD 500 MHz spectrometer. The (CH3)4Si signal was used as a reference. The purities of gold–NHC complexes were detected at the instrumental analysis center of China Pharmaceutical University and obtained on a PE 2400 Series II instrument. HPLC analysis was performed on a Waters ACQUITY Arc system equipped with a 2998 PDA detector. UV–vis spectra were recorded on a Shimadzu UV2400 spectrophotometer. The MALDI-TOF/TOF mass spectrometer used was a Bruker Daltonics ultrafl extreme MALDI TOF/TOF instrument. X-ray single crystal diffractometry measurements was recorded by a BRUKER Smart APEX II CCD instrument. The flow cytometer used in the cell cycle and apoptosis experiments was a BD C6 Plus instrument. The fluorescence spectra were detected by a Hitachi fluorescence spectrophotometer, model F-7000.

4.2. Synthesis and Characterization

4.2.1. The Synthesis of Chloro–Gold(I)–NHC complexes 1 and 2

A mixture of imidazolium salts a (786.4 mg, 2 mmol) or b (834.7 mg, 2 mmol) and silver oxide (278.1 mg, 1.2 mmol) in CH2Cl2 (20 mL) was stirred overnight under a N2 atmosphere. Then, (Me2S)AuCl (589.1 mg, 2 mmol) was added, and the mixture was kept in the same conditions to continue the reaction for 6 h. The reaction mixture was filtered through Celite, and the filtrate was condensed in vacuo to acquire the crude product. The crude product was further purified by a chromatography column and recrystallized from CH2Cl2/n-hexane to yield a white solid.
4.2.2. Chloro(1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene)gold(I) (1)
Yield 84%. 1H NMR (500 MHz, CDCl3, 20 °C): δ 7.16 (dd, J = 8.7, 5.2 Hz, 4H, ArH), 7.05 (t, J = 8.5 Hz, 4H, ArH), 4.15 (q, J = 7.2 Hz, 4H, NCH2CH3), 1.28 (t, J = 7.2 Hz, 6H, NCH2CH3). 13C NMR (126 MHz, CDCl3, 20 °C): δ 169.68 (NCN–Au), 164.18, 162.19, 132.42, 132.35, 123.49, 123.46, 116.40, 116.22 (ArC), 130.34 (NC=CN), 44.44 (NCH2CH3), 16.90 (NCH2CH3). MALDI-TOF/TOF-MS: 544.228 [M]+, 567.077 [M + Na]+, 583.050 [M + K]+. Anal. Calcd for C19H18AuClF2N2: C, 41.89; H, 3.33; N, 5.14. Found: C, 41.81; H, 3.14; N, 4.99.
4.2.3. Chloro(1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene)gold(I) (2)
Yield 53%. 1H NMR (500 MHz, CDCl3, 20 °C): δ 7.11 (d, J = 8.5 Hz, 4H, ArH), 6.87 (d, J = 8.6 Hz, 4H, ArH), 4.16 (q, J = 7.1 Hz, 4H, NCH2CH3), 3.80 (s, 6H, ArOCH3), 1.30 (t, J = 7.2 Hz, 6H, NCH2CH3). 13C NMR (126 MHz, CDCl3, 20 °C): δ 168.55 (NCN–Au), 160.14, 131.80, 119.87, 114.30 (ArC), 130.76 (NC=CN), 55.27 (ArOCH3), 44.25 (NCH2CH3), 16.93 (NCH2CH3). MALDI-TOF/TOF-MS: 568.104 [M]+, 533.172 [M – Cl]+, 591.133 [M + Na]+. Anal. Calcd for C21H24AuClN2O2: C, 44.34; H, 4.25; N, 4.92. Found: C, 44.03; H, 4.02; N, 4.74.

4.2.4. The Synthesis of Gold(I)–NHC complexes 3–6

1 (60 mg, 0.11 mmol) and sodium bromide (45.3 mg, 0.44 mmol) or potassium iodide (73.1 mg, 0.44 mmol) were dissolved in 2 mL of anhydrous acetone, and the mixture was stirred under N2 for 24 h to form 3 or 5, respectively. Meanwhile, 2 (60 mg, 0.105 mmol) and sodium bromide (43.4 mg, 0.42 mmol) or potassium iodide (70 mg, 0.42 mmol) were dissolved in 2 mL of anhydrous acetone, and the mixture was stirred under N2 for 24 h to form 4 or 6, respectively. After the solvent was removed in vacuo, the residue was dissolved in CH2Cl2 and then filtered over a bed of Celite. The filtrate was carefully evaporated to dryness under reduced pressure to yield a colorless solid, which was further purified through a plug of silica.
4.2.5. Bromo(1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene)gold(I) (3)
Yield 59%. 1H NMR (500 MHz, CDCl3, 20 °C): δ 7.23–7.18 (m, 4H, ArH), 7.12–7.07 (m, 4H, ArH), 4.20 (q, J = 7.2 Hz, 4H, NCH2CH3), 1.33 (t, J = 7.2 Hz, 6H, NCH2CH3). 13C NMR (126 MHz, CDCl3, 20 °C): δ 173.28 (NCN–Au), 164.18, 162.16, 132.41, 132.34, 123.49, 123.47, 116.40, 116.23 (ArC), 130.27 (NC=CN), 44.33 (NCH2CH3), 16.90 (NCH2CH3).
4.2.6. Bromo(1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene)gold(I) (4)
Yield 63%. 1H NMR (500 MHz, CDCl3, 20 °C): δ 7.11 (d, J = 8.7 Hz, 4H, ArH), 6.87 (d, J = 8.7 Hz, 4H, ArH), 4.16 (q, J = 7.2 Hz, 4H, NCH2CH3), 3.80 (s, 6H, ArOCH3), 1.30 (t, J = 7.2 Hz, 6H, NCH2CH3). 13C NMR (126 MHz, CDCl3, 20 °C): δ 172.07 (NCN–Au), 160.11, 131.78, 119.86, 114.28 (ArC), 130.68 (NC=CN), 55.26 (ArOCH3), 44.15 (NCH2CH3), 16.94 (NCH2CH3).
4.2.7. Iodo(1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene)gold(I) (5)
Yield 48.3%. 1H NMR (500 MHz, CDCl3, 20 °C): δ 7.19 (dd, J = 8.5, 5.3 Hz, 4H, ArH), 7.08 (t, J = 8.5 Hz, 4H, ArH), 4.19 (q, J = 7.2 Hz, 4H, NCH2CH3), 1.32 (t, J = 7.2 Hz, 6H, NCH2CH3). 13C NMR (126 MHz, CDCl3, 20 °C): δ 180.29 (NCN–Au), 164.16, 162.16, 132.41, 132.35, 123.51, 123.48, 116.39, 116.22 (ArC), 130.17 (NC=CN), 44.08 (NCH2CH3), 16.94 (NCH2CH3). MALDI-TOF/TOF-MS: 509.137 [M – I]+. Anal. Calcd for C19H18AuF2IN2: C, 35.87; H, 2.85; N, 4.40. Found: C, 35.96; H, 2.65; N, 4.28.
4.2.8. Iodo(1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene)gold(I) (6)
Yield 58%. 1H NMR (500 MHz, CDCl3, 20 °C): δ 7.13 (d, J = 8.7 Hz, 4H, ArH), 6.88 (d, J = 8.7 Hz, 4H, ArH), 4.18 (q, J = 7.2 Hz, 4H, NCH2CH3), 3.81 (s, 6H, ArOCH3), 1.33 (t, J = 7.2 Hz, 6H, NCH2CH3). 13C NMR (126 MHz, CDCl3, 20 °C): δ 179.24 (NCN–Au), 160.10, 131.77, 119.87, 114.29 (ArC), 130.56 (NC=CN), 55.27 (ArOCH3), 43.90 (NCH2CH3), 16.97 (NCH2CH3). MALDI-TOF/TOF-MS: 533.180 [M – I]+, 679.549 [M + H3O]+. Anal. Calcd for C21H24AuClN2O2: C, 44.34; H, 4.25; N, 4.92. Found: C, 44.03; H, 4.02; N, 4.74.

4.2.9. The Synthesis of Cyanato–Gold(I)–NHC Complexes 7 and 8

Silver nitrate (31.1 mg, 0.183 mmol) was dissolved in a mixture solution comprised of 0.3 mL of CH3OH and 0.1 mL of H2O and then slowly added to a mixture (3 mL of CH3OH/0.6 mL of H2O) with potassium cyanate (35.7 mg, 0.44 mmol) and 1 (60 mg, 0.11 mmol) or 2 (62.7 mg, 0.11 mmol), which immediately gave a white precipitate. The reaction mixture was stirred for 15 min and then filtered, and the filtrate was carefully evaporated in vacuo. The residue was recrystallized from CH2Cl2/n-hexanes to yield a white solid.
4.2.10. Cyanato(1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene)gold(I) (7)
Yield 49%. 1H NMR (500 MHz, CDCl3, 20 °C): δ 7.19 (dd, J = 8.5, 5.3 Hz, 4H, ArH), 7.07 (t, J = 8.5 Hz, 4H, ArH), 4.15 (q, J = 7.2 Hz, 4H, NCH2CH3), 1.32 (t, J = 7.2 Hz, 6H, NCH2CH3). 13C NMR (126 MHz, CDCl3, 20 °C): δ 167.71 (NCN–Au), 164.20, 162.20, 132.47, 132.40, 123.49, 123.46, 116.38, 116.21 (ArC), 130.47 (NC=CN), 129.43 (NCO), 44.46 (NCH2CH3), 16.91 (NCH2CH3). MALDI-TOF/TOF-MS: 509.129 [M – NCO]+, 526.157 [M – CNO + OH]+. Anal. Calcd for C20H18AuF2N3O: C, 43.57; H, 3.29; N, 7.62. Found: C, 43.52; H, 3.33; N, 7.21.
4.2.11. Cyanato(1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene)gold(I) (8)
Yield 43%. 1H NMR (500 MHz, CDCl3, 20 °C): δ 7.10 (d, J = 8.5 Hz, 4H, ArH), 6.87 (d, J = 8.6 Hz, 4H, ArH), 4.13 (q, J = 7.2 Hz, 4H, NCH2CH3), 3.80 (s, 6H, ArOCH3), 1.30 (t, J = 7.2 Hz, 6H, NCH2CH3). 13C NMR (126 MHz, CDCl3, 20 °C): δ 166.54 (NCN–Au), 160.14, 131.79, 119.80, 114.30 (ArC), 130.88 (NC=CN), 129.48 (NCO), 55.27 (ArOCH3), 44.27 (NCH2CH3), 16.97 (NCH2CH3). MALDI-TOF/TOF-MS: 533.162 [M – NCO]+, 550.193 [M – NCO + OH]+. Anal. Calcd for C22H24AuN2O3: C, 45.92; H, 4.20; N, 7.30. Found: C, 45.84; H, 4.10; N, 7.30.

4.2.12. The Synthesis of Acetate–Gold(I)–NHC Complexes 9 and 10

A mixture of silver acetate (40.5 mg, 0.242 mmol) and 1 (57.2 mg, 0.105 mmol) or 2 (60 mg, 0.105 mmol) in CH2Cl2 (5 mL) was stirred for 1 h. The mixture was filtered over a bed of Celite, and the filtrate was evaporated to yield a white solid.
4.2.13. Acetato(1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene)gold(I) (9)
Yield 67%. 1H NMR (500 MHz, CDCl3, 20 °C): δ 7.16 (dd, J = 8.5, 5.3 Hz, 4H, ArH), 7.07 (t, J = 8.5 Hz, 4H, ArH), 4.18 (q, J = 7.2 Hz, 4H, NCH2CH3), 2.09 (s, 3H, CH3COO) 1.33 (t, J = 7.2 Hz, 6H, NCH2CH3). 13C NMR (126 MHz, CDCl3, 20 °C): δ 177.47 (CH3COO), 162.85 (NCN–Au), 164.16, 162.17, 132.41, 132.34, 123.53, 123.50, 116.38, 116.20 (ArC), 130.44 (NC=CN), 44.53 (NCH2CH3), 23.85 (CH3COO), 16.85 (NCH2CH3). MALDI-TOF/TOF-MS: 509.127 [M – OAc]+, 526.154 [M – OAc + OH]+. Anal. Calcd for C21H21AuF2N2O2: C, 44.38; H, 3.72; N, 4.93. Found: C, 44.47; H, 3.52; N, 4.78.
4.2.14. Acetato(1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene)gold(I) (10)
Yield 75%. 1H NMR (500 MHz, CDCl3, 20 °C): δ 7.09 (d, J = 8.7 Hz, 4H, ArH), 6.86 (d, J = 8.7 Hz, 4H, ArH), 4.16 (q, J = 7.2 Hz, 4H, NCH2CH3), 3.80 (s, 6H, ArOCH3), 2.09 (s, 3H, CH3COO), 1.32 (t, J = 7.2 Hz, 6H, NCH2CH3). 13C NMR (126 MHz, CDCl3, 20 °C): δ 177.51 (CH3COO), 161.52(NCN–Au), 160.11, 131.81, 119.93, 114.28 (ArC), 130.89 (NC=CN), 55.26 (ArOCH3), 44.35 (NCH2CH3), 23.89 (CH3COO), 16.89 (NCH2CH3). MALDI-TOF/TOF-MS: 533.167 [M – OAc]+, 550.196 [M – OAc + OH]+. Anal. Calcd for C23H27AuN2O4: C, 46.63; H, 4.59; N, 4.73. Found: C, 46.51; H, 4.52; N, 4.89.

4.3. X-ray Crystallographic Analysis

Single crystal X-ray diffraction data of complex 6 were collected on a Bruker Smart APEX II CCD area-detector diffractometer with graphite-monochromated Mo Kα radiation (0.71073 Å). More detailed data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures using CCDC number 1973303 or DOI 10.5517/ccdc.csd.cc247cyq.

4.4. Stability Analysis

4.4.1. 1H NMR assay

The NHC–gold(I) complex 6 was dissolved in acetone-d6 or an acetone-d6 solution containing 10% D2O at a concentration of 10 mM. The solutions were transferred to an NMR tube and detected by 1H NMR spectra at different times (0–5 days).

4.4.2. UV–Vis Assay

The stability of 2, 4, and 6 (20 μM) in PBS (pH 7.28) with a high concentration of GSH (2 mM) was studied by UV–vis spectrometry via a Shimadzu UV2400 spectrophotometer.

4.5. Growth Inhibitory Assay

All compounds, including cisplatin and auranofin, were dissolved in DMF. They were subsequently diluted to their final assay concentrations (0.1% v/v DMF) before treatment of the cultured cells. HCC (HepG2, SMMC-7721, or Hep3B) cells and noncancerous cells (LO2 and H8) were seeded into 96-well plates (2 × 103 per well). The cells were cultured overnight in DMEM supplemented with 10% FBS. Then, after the addition of different concentrations of compounds and the negative control (0.1% DMF), cells were incubated at 37 °C for 72 h.
The antiproliferative effects of the compounds were tested by the MTT assay by adding 5% MTT (5 mg/mL, PBS) reagent to the cells and incubating the mixture for about 4 h. Then, supernatant was discarded, 200 μL of DMSO was added, and the mixture was shaken for about 10 min. Finally, the absorbance was detected at 490 nm. The XTT assay (cell signaling no. 9095) was performed according to the protocol. In brief, the medium containing XTT and the electron-coupling reagent reacted for 4 h. The absorbance of the wells was determined at 450 nm. The growth inhibitory rates of the compounds were calculated by XTT assays as (Ac – As)/(Ac – Ab) × 100% (Ac, absorbance of control wells; As, absorbance of sample wells; and Ab, Absorbance of blank wells). LDH assays were used to test the cell death as cell death (%) = (As – Ac)/(Am – Ac) × 100 (As, absorbance of sample wells; Ac, absorbance of control wells; and Am, absorbance of the maximum enzyme activity wells). The IC50 values corresponding to the concentration that caused 50% of the inhibition of the cell proliferation were calculated using Graphpad Prism 5 statistical analysis.
After incubation with the target compounds under hypoxic conditions (1% O2, 5% CO2, and 94% N2 at 37 °C) for 72 h, cytotoxicity of the cells was measured.

4.6. Purified TrxR Enzyme Assay

TrxR activity was detected by the NADPH-dependent reduction of DTNB at room temperature. Briefly, different concentrations of gold complex 6 were dissolved in DMF and diluted with the respective buffers. Next, 25 μL of rat liver TrxR buffer (0.15 U) and 25 μL of DMF containing the complexes were added into the 96-well plates. Then, to each well was added 225 μL of the reaction mixture. DTNB (20 mM) was added into the solution. After fully mixing, the absorption data was recorded at 405 nm with a microplate reader, and the enzyme activity was calculated as its slope.

4.7. Quantitative Real-Time PCR

According to the protocol, real-time PCR was executed by a 7500 RT-PCR system as described previously. (50) The following primers (GenScript) were used:

  • β-actin (forward): 5′-TGTG-GATC-AGCA-AGCA-GGAG-TA-3′,

  • β-actin (reverse): 5′-TGCG-CAAG-TTAG-GTTT-TGTCA-3′.

  • TrxR (forward): 5′-GCCC-TGCA-AGAC-TCTC-GAAA-TTA-3′,

  • TrxR (reverse): 5′-GCCC-ATAA-GCAT-TCTC-ATAG-ACGA-3′.

4.8. Cellular Activities of the TrxR Assay

HepG2 cells were treated with complex 6 and incubated for 48 and 72 h. The total cell protein was extracted in an ice bath and determined from the protein concentration by BCA assays. TrxR activity in the cells was tested by the TrxR activity detection kit.

4.9. Immunofluorescence Staining

The experiments were carried out according to the protocol. (58) In brief, HepG2 cells were treated with complex 6 for 24 h. Different antibodies were incubated overnight at 4 °C. PBS was used to wash the cells, and then they were treated with the secondary antibody for 2 h. Finally, a fluorescence microscope was used to detect the change of fluorescence.

4.10. Western Blot Analysis

HepG2 cell extracts were prepared by washing the cells in cold PBS, followed by resuspension in the cell lysis buffer. Cell lysis buffers were separated by a 12.5% SDS-PAGE gel. After the separation process, the proteins were imprinted onto the PVDF membranes and probed with various specific antibodies. Then, they were washed and incubated with the antirabbit or antimouse for 2 h. The bands of protein were detected by a chemiluminescence procedure (ECL, Amersham).

4.11. Intracellular ROS Measurement

Cells were incubated with complex 6 at different concentrations for 12 h. Then, they were washed and treated in darkness with either 10 μM CM-DCFH2-DA or 20 μM DHE for 20 min at 37 °C. The increase of fluorescence was tested by fluorescent microscopy.

4.12. Measurement of MMP

Cells were seeded in a 24-well plate and then treated with either complex 6 or DMF for 24 h. After that, the cells were treated with JC-1 (5 μM) for 30 min. The cell staining was detected by fluorescence microscopy.

4.13. Cell Cycle Arrest and Apoptosis Analysis

HepG2 cells were treated with either DMF or complex 6 at different concentrations for 72 h. In brief, either DNA flow cytometric kits or annexin V-FITC apoptosis assay kits were used to determine the stage of the cell cycle and apoptosis according to the protocol by flow cytometry.

4.14. Animals

The animal experiments were performed in accordance with the Act on Experimental Work with Animals. All mice were maintained in specific pathogen-free conditions. All mice experiments were performed in compliance with the guidelines and protocols, which were approved by the institutional and local ethics committee of Nanjing University of Chinese Medicine.

4.15. Tumor Nude Mice Model

Male BALB/c nude mice (18–22 g) were inoculated with HepG2 cells (1.5 × 107per mouse). Once the tumor reached 180–200 mm3, the mice were split into three groups (n = 4) at random. Then, complex 6 (5 mg/kg), cisplatin (5 mg/kg), or the same volume of normal saline intraperitoneally administered for 15 days. Using a digital caliper to gauge the tumor size and calculate the tumor volume (TV), the following formula was used: TV (mm3) = width (2) × (length/2). The inhibition rates of tumor growth (IRT) were calculated as follows: IRT = 100% × (M1 – M2)/M1, where M1 and M2 are the tumor weights in the control group and the drug treatment group, respectively.

4.16. Chronic HCC Model Caused by CCl4

Four week old male ICR mice (18–22 g) were randomly divided into four groups (n = 5). Group one was the vehicle control, group two was the CCl4 model group, group three was the complex 6 treatment group, and group four was the positive control group (cisplatin). Groups two through four were intraperitoneally injected with CCl4 (5 mL/kg) three times every week and treated for 16 weeks to induce HCC. Groups three and four were treated with complex 6 (5 mg/kg) and cisplatin (5 mg/kg), respectively, daily for two weeks. After 16 weeks, liver tissues and blood samples were collected, and the liver tissues were fixed in a 4% paraformaldehyde buffer.

4.17. Enzyme-linked Immunosorbent Assay (ELISA)

ELISA kits were used to measure the serum levels of TrxR (Nanjing Sen Bei Jia).

4.18. Biochemical Analysis

Serum samples were separated and used for LDH, ALT, and AST tests (Beyotime Biotechnology). The plate reader (PerkinElmer Fusion Reader) was used to measure the absorbance values according to the manufacturer’s protocol.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00257.

  • Stability information, antiproliferative effects, cell death effects, and additional data and spectra (PDF)

  • Molecular formula strings and biological data (CSV)

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Author Information

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  • Corresponding Author
    • Wukun Liu - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China;  State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China;  State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210023, P. R. China;  Orcidhttp://orcid.org/0000-0002-0469-907X;  Email: [email protected] [email protected]
  • Authors
    • Mianli Bian - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
    • Rong Fan - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
    • Guizhi Jiang - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
    • Yingxiang Wang - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
    • Yunlong Lu - Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Pharmacy, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
  • Author Contributions

    M.B. and R.F. contributed equally to this work.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The authors thank the financial support from the National Natural Science Foundation of China (NSFC) (Grant 81703337); the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine); the Jiangsu Specially-Appointed Professors program; the Six Talent Peaks Project in the Jiangsu Province of China (Grant SWYY-069); the State Key Laboratory of Coordination Chemistry; Nanjing University; and the Open Project of State Key Laboratory of Natural Medicines, China Pharmaceutical University (Grants SKLNMKF201712 and SKLNMKF201808).

Abbreviations Used
ALT

alanine aminotransferase

AST

aspartate aminotransferase

CCl4

carbon tetrachloride

CDKs

cyclin dependent protein kinase

CT-DNA

calf thymus DNA

DHE

dihydroethidium

IRT

rate of tumor growth

HCC

hepatocellular carcinoma

LDH

lactate dehydrogenase

IL-1β

Interleukin-1β

MMP

mitochondrial membrane potential

NAC

N-acetylcysteine

PBS

phosphate buffer solution

ROS

reactive oxygen species

TNF-α

tumor necrosis factor

TrxR

thioredoxin reductase

References

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This article references 58 other publications.

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    Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide which lacks effective treatment. Cancer cells experience high levels of oxidative stress due to increased generation of reactive oxygen species (ROS). Increased antioxidant-producing capacity is therefore found in cancer cells to counteract oxidative stress. The thioredoxin system is a ubiquitous mammalian antioxidant system which scavenges ROS, and we demonstrate that it is vital for HCC growth as it maintains intracellular redn.-oxidn. (redox) homeostasis. Transcriptome sequencing in human HCC samples revealed significant overexpression of thioredoxin reductase 1 (TXNRD1), the cytosolic subunit and key enzyme of the thioredoxin system, with significant correlations to poorer clinicopathol. features and patient survival. Driven by the transcriptional activation of nuclear factor (erythroid-derived 2)-like 2, the master protector against oxidative stress, TXNRD1 counteracts intracellular ROS produced in human HCC. Inhibition of TXNRD1 through genetic inhibition hindered the proliferation of HCC cells and induced apoptosis in vitro. Administration of the pharmacol. TXNRD1 inhibitor auranofin (AUR) effectively suppressed the growth of HCC tumors induced using the hydrodynamic tail vein injection and orthotopic implantation models in vivo. Furthermore, AUR sensitized HCC cells toward the conventional therapeutic sorafenib. Conclusion: Our study highlights the reliance of HCC cells on antioxidants for redox homeostasis and growth advantage; targeting TXNRD1 resulted in dramatic accumulation of ROS, which was found to be an effective approach for the suppression of HCC tumor growth.
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  14. 14
    Rackham, O.; Shearwood, A. M.; Thyer, R.; McNamara, E.; Davies, S. M.; Callus, B. A.; Miranda-Vizuete, A.; Berners-Price, S. J.; Cheng, Q.; Arner, E. S.; Filipovska, A. Substrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: implications for development of specific inhibitors. Free Radical Biol. Med. 2011, 50, 689– 699,  DOI: 10.1016/j.freeradbiomed.2010.12.015
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    Substrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: Implications for development of specific inhibitors
    Rackham, Oliver; Shearwood, Anne-Marie J.; Thyer, Ross; McNamara, Elyshia; Davies, Stefan M. K.; Callus, Bernard A.; Miranda-Vizuete, Antonio; Berners-Price, Susan J.; Cheng, Qing; Arner, Elias S. J.; Filipovska, Aleksandra
    Free Radical Biology & Medicine (2011), 50 (6), 689-699CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
    The cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) and thioredoxins (Trx1 and Trx2) are key components of the mammalian thioredoxin system, which is important for antioxidant defense and redox regulation of cell function. TrxR1 and TrxR2 are selenoproteins generally considered to have comparable properties, but to be functionally sepd. by their different compartments. To compare their properties we expressed recombinant human TrxR1 and TrxR2 and detd. their substrate specificities and inhibition by metal compds. TrxR2 preferred its endogenous substrate Trx2 over Trx1, whereas TrxR1 efficiently reduced both Trx1 and Trx2. TrxR2 displayed strikingly lower activity with dithionitrobenzoic acid (DTNB), lipoamide, and the quinone substrate juglone compared to TrxR1, and TrxR2 could not reduce lipoic acid. However, Sec-deficient two-amino-acid-truncated TrxR2 was almost as efficient as full-length TrxR2 in the redn. of DTNB. We found that the gold(I) compd. auranofin efficiently inhibited both full-length TrxR1 and TrxR2 and truncated TrxR2. In contrast, some newly synthesized gold(I) compds. and cisplatin inhibited only full-length TrxR1 or TrxR2 and not truncated TrxR2. Surprisingly, one gold(I) compd., [Au(d2pype)2]Cl, was a better inhibitor of TrxR1, whereas another, [(iPr2Im)2Au]Cl, mainly inhibited TrxR2. These compds. also inhibited TrxR activity in the cytoplasm and mitochondria of cells, but their cytotoxicity was not always dependent on the proapoptotic proteins Bax and Bak. In conclusion, this study reveals significant differences between human TrxR1 and TrxR2 in substrate specificity and metal compd. inhibition in vitro and in cells, which may be exploited for development of specific TrxR1- or TrxR2-targeting drugs.
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    Li, C.; Peng, Y.; Mao, B.; Qian, K. Thioredoxin reductase: a novel, independent prognostic marker in patients with hepatocellular carcinoma. Oncotarget 2015, 6, 17792– 17804,  DOI: 10.18632/oncotarget.3785
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    15
    Thioredoxin reductase: a novel, independent prognostic marker in patients with hepatocellular carcinoma
    Li Chunyan; Li Chunyan; Peng Yan; Mao Binglang; Qian Kun
    Oncotarget (2015), 6 (19), 17792-804 ISSN:.
    Here we found that hepatocellular carcinoma (HCC) patients with recurrence outcome and nonsurvivors had significantly increased thioredoxin reductase (TrxR) serum levels on reoperation (P < 0.0001 and P < 0.0001). Multivariate regression analysis adjusted for common risk factors showed that TrxR was an independent predictor of recurrence (hazard ratios [HR] = 4.19; 95% confidence intervals [CI]: 3.21-7.08) and overall survival (HR = 5.56; 95% CI: 3.42-10.21). The area under the receiver operating characteristic curve of TrxR was 0.837 (95% CI, 0.794-0.881) for recurrence outcome and 0.901 (95% CI, 0.869-0.933) for mortality, which was superior to high-sensitivity-C-reactive protein and a-fetoprotein (P < 0.001). The preoperative serum TrxR level is an independent and significant indicator predictive of poor prognosis and early recurrence in patients with HCC, which offering reliable information for predicting survival.
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  16. 16
    Zheng, X.; Ma, W.; Sun, R.; Yin, H.; Lin, F.; Liu, Y.; Xu, W.; Zeng, H. Butaselen prevents hepatocarcinogenesis and progression through inhibiting thioredoxin reductase activity. Redox Biol. 2018, 14, 237– 249,  DOI: 10.1016/j.redox.2017.09.014
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    Butaselen prevents hepatocarcinogenesis and progression through inhibiting thioredoxin reductase activity
    Zheng, Xiaoqing; Ma, Weiwei; Sun, Ruoxuan; Yin, Hanwei; Lin, Fei; Liu, Yuxi; Xu, Wei; Zeng, Huihui
    Redox Biology (2018), 14 (), 237-249CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)
    Hepatocellular carcinoma (HCC) accounts for most of primary liver cancer, of which five-year survival rate remains low and chemoprevention has become a strategy to reduce disease burden of HCC. We aim to explore the in vivo chemopreventive effect of an organoselenium-contg. compd. butaselen (BS) against hepatocarcinogenesis and its underlying mechanisms. Pre- and sustained BS treatment (9, 18 and 36 mg/Kg BS) could dose-dependently inhibit chronic hepatic inflammation, fibrosis, cirrhosis and HCC on murine models with 24 wk treatment scheme. The thioredoxin reductase (TrxR), NF-κB pathway and pro-inflammatory factors were activated during hepatocarcinogenesis, while their expression were decreased by BS treatment. BS treatment could also significantly reduce tumor vol. in H22-bearing models and remarkably slow tumor growth. HCC cell lines HepG2, Bel7402 and Huh7 were time- and dose-dependently inhibited by BS treatment. G2/M arrest and apoptosis were obsd. in HepG2 cells after BS treatment, which were mediated by TrxR/Ref-1 and NF-κB pathways inhibition. BS generated reactive oxygen species (ROS), which could be reduced by antioxidant N-acetyl-L-cysteine (NAC) and NADPH oxidase inhibitor DPI. NAC could markedly increase HepG2 cells viability. TrxR activity of HepG2 cells treated with BS were significantly decreased in parallel with proliferative inhibition. The TrxR1-knockdown HepG2 cells also exhibited low TrxR1 activity, high ROS level, relatively low proliferation rate and increased resistance to BS treatment. In conclusion, BS can prevent hepatocarcinogenesis through inhibiting chronic inflammation, cirrhosis and tumor progression. The underlying mechanisms may include TrxR activity inhibition, leading to ROS elevation, G2/M arrest and apoptosis.
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    Zhang, L.; Cheng, Q.; Zhang, L.; Wang, Y.; Merrill, G. F.; Ilani, T.; Fass, D.; Arnér, E. S. J.; Zhang, J. Serum thioredoxin reductase is highly increased in mice with hepatocellular carcinoma and its activity is restrained by several mechanisms. Free Radical Biol. Med. 2016, 99, 426– 435,  DOI: 10.1016/j.freeradbiomed.2016.08.028
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    Serum thioredoxin reductase is highly increased in mice with hepatocellular carcinoma and its activity is restrained by several mechanisms
    Zhang, Le; Cheng, Qing; Zhang, Longjie; Wang, Yijun; Merrill, Gary F.; Ilani, Tal; Fass, Deborah; Arner, Elias S. J.; Zhang, Jinsong
    Free Radical Biology & Medicine (2016), 99 (), 426-435CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
    Increased thioredoxin reductase (TrxR) levels in serum were recently identified as possible prognostic markers for human prostate cancer or hepatocellular carcinoma. We had earlier shown that serum levels of TrxR protein are very low in healthy mice, but can in close correlation to alanine aminotransferase (ALT) increase more than 200-fold upon chem. induced liver damage. We also found that enzymic TrxR activity in serum is counteracted by a yet unidentified oxidase activity in serum. In the present study we found that mice carrying H22 hepatocellular carcinoma tumors present highly increased levels of TrxR in serum, similarly to that reported in human patients. In this case ALT levels did not parallel those of TrxR. We also discovered here that the TrxR-antagonistic oxidase activity in serum is due to the presence of quiescin Q6 sulfhydryl oxidase 1 (QSOX1). We furthermore found that the chemotherapeutic agents cisplatin or auranofin, when given systemically to H22 tumor bearing mice, can further inhibit TrxR activities in serum. The TrxR serum activity was also inhibited by endogenous electrophilic inhibitors, found to increase in tumor-bearing mice and to include protoporphyrin IX (PpIX) and 4-hydroxynonenal (HNE). Thus, hepatocellular carcinoma triggers high levels of serum TrxR that are not paralleled by ALT, and TrxR enzyme activity in serum is counteracted by several different mechanisms. The physiol. role of TrxR in serum, if any, as well as its potential value as a prognostic marker for tumor progression, needs to be studied further.
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    Bertrand, B.; Williams, M. R. M.; Bochmann, M. Gold(III) complexes for antitumor applications: an overview. Chem. - Eur. J. 2018, 24, 11840– 11851,  DOI: 10.1002/chem.201800981
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    Gold(III) Complexes for Antitumor Applications: An Overview
    Bertrand, Benoit; Williams, Morwen R. M.; Bochmann, Manfred
    Chemistry - A European Journal (2018), 24 (46), 11840-11851CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Gold(III) complexes have emerged as a versatile and effective class of metal-based anticancer agents. The development of various types of ligands capable of stabilizing the AuIII cation and preventing its redn. under physiol. conditions, such as chelating nitrogen-donors, dithiocarbamates and ĈN cyclometalled ligands, has opened the way for the exploration of their potential intracellular targets and action mechanisms. At the same time, the bioconjugation of AuIII complexes has emerged as a promising strategy for improving the selectivity of this class of compds. for cancer cells over healthy tissues, and recent developments have shown that combining gold complexes with mol. structures that are specifically recognized by the cell can exploit the cell's own transport mechanisms to improve selective metal uptake.
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    Gust, R.; Ott, I.; Posselt, D.; Sommer, K. Development of cobalt(3,4-diarylsalen) complexes as tumor therapeutics. J. Med. Chem. 2004, 47, 5837– 5846,  DOI: 10.1021/jm040763n
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    Development of Cobalt(3,4-diarylsalen) Complexes as Tumor Therapeutics
    Gust, Ronald; Ott, Ingo; Posselt, Diana; Sommer, Klaus
    Journal of Medicinal Chemistry (2004), 47 (24), 5837-5846CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    [1,6-Bis(2-hydroxyphenyl)-3,4-diaryl-2,5-diazahexa-1,5-diene]cobalt(II) complexes (cobalt(3,4-diarylsalen)) with 2-, 3-, or 4-OCH3/OH substituents in the 3,4-standing aryl rings were synthesized and tested for antitumor activity in vitro on the MCF-7, MDA-MB 231, and LNCaP/FGC cell lines. The cytotoxicity depended on both the configuration of the diene ligand and the kind of substituents in the 3,4-standing arom. rings. D,l-7 (2-OCH3), d,l-8 (3-OCH3), and d,l-9 (4-OCH3) were equipotent to cisplatin, while the resp. hydroxy-substituted complexes (d,l-10 (2-OH), d,l-11 (3-OH), and d,l-12 (2-OH)) as well as all of the meso-configured compds. (m-7 to m-12) did not influence the cell growth. Interestingly, a high catalytic potency and a rapid and high accumulation in MCF-7 cells (15- to 25-fold compared to the cell culture medium (5 μM)) were demonstrated for m-7 (2-OCH3), m-8 (3-OCH3), and m-9 (4-OCH3). Therefore, a mode of action based on a cobalt-catalyzed oxidative damage of the DNA is not very likely.
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    Ott, I. On the medicinal chemistry of gold complexes as anticancer drugs. Coord. Chem. Rev. 2009, 253, 1670– 1681,  DOI: 10.1016/j.ccr.2009.02.019
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    On the medicinal chemistry of gold complexes as anticancer drugs
    Ott, Ingo
    Coordination Chemistry Reviews (2009), 253 (11+12), 1670-1681CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
    A review. Metal complexes have shown interesting preclin. and clin. results as antitumor drugs and platinum compds. are well established in current cancer chemotherapy. However, the platinum based treatment of tumoral diseases is massively hampered by severe side effects and resistance development. Consequently, the development of novel metallodrugs with a pharmacol. profile different from that of the platinum drugs is in the focus of modern medicinal chem. and drug design. Among the non-platinum antitumor drugs, gold complexes have recently gained considerable attention due to their strong antiproliferative potency. In many cases the cell growth inhibiting effects could be related to anti-mitochondrial effects making gold species interesting drug candidates with a mode of action different from that of the platinum agents. The spectrum of gold complexes described as antiproliferative compds. comprises a broad variety of different species including many phosphine complexes as well as gold in different oxidn. states. This presentation gives an overview of the relevant medicinal chem. of known gold complexes with in vitro and in vivo tumor growth inhibiting properties.
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    Schmidt, C.; Karge, B.; Misgeld, R.; Prokop, A.; Bronstrup, M.; Ott, I. Biscarbene gold(i) complexes: structure-activity-relationships regarding antibacterial effects, cytotoxicity, TrxR inhibition and cellular bioavailability. MedChemComm 2017, 8, 1681– 1689,  DOI: 10.1039/C7MD00269F
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    Biscarbene gold(I) complexes: structure-activity-relationships regarding antibacterial effects, cytotoxicity, TrxR inhibition and cellular bioavailability
    Schmidt, Claudia; Karge, Bianka; Misgeld, Rainer; Prokop, Aram; Broenstrup, Mark; Ott, Ingo
    MedChemComm (2017), 8 (8), 1681-1689CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
    A series of gold(I) complexes with two N-heterocyclic carbene ligands (biscarbene gold complexes) were prepd. and evaluated for their effects against cancer cells and pathogenic bacteria. Proliferation inhibition was obsd. in cancer cells and in Gram-pos. bacteria, whereas Gram-neg. bacteria were less sensitive towards the compds. The protein binding and cellular uptake were quantified and the combined results indicated a strong correlation between cellular bioavailability and antiproliferative effects. The biscarbene gold complexes inhibited bacterial and mammalian TrxRs with low to moderate potency. However, based on the obtained structure-activity-relationships and the high cellular accumulation levels, TrxR inhibition can be considered as a relevant contributor to the cellular pharmacol. of biscarbene gold(I) complexes.
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    Liu, W.; Bensdorf, K.; Proetto, M.; Abram, U.; Hagenbach, A.; Gust, R. NHC gold halide complexes derived from 4,5-diarylimidazoles: synthesis, structural analysis, and pharmacological investigations as potential antitumor agents. J. Med. Chem. 2011, 54, 8605– 8615,  DOI: 10.1021/jm201156x
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    22
    NHC Gold halide complexes derived from 4,5-diarylimidazoles: synthesis, structural analysis, and pharmacological investigations as potential antitumor agents
    Liu, Wukun; Bensdorf, Kerstin; Proetto, Maria; Abram, Ulrich; Hagenbach, Adelheid; Gust, Ronald
    Journal of Medicinal Chemistry (2011), 54 (24), 8605-8615CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A series of novel neutral N-heterocyclic carbene (NHC) gold halide complexes derived from 4,5-diarylimidazoles were synthesized, characterized, and analyzed for biol. effects. High growth inhibitory effects in MCF-7 and MDA-MB 231 breast cancer as well as HT-29 colon cancer cell lines depended on the presence of the C4,C5-standing arom. rings. Methoxy groups at these rings did not change the growth inhibitory properties, while F-substituents in the ortho-position increased the activity in MCF-7 and MDA-MB 231 cells. The substituents at the nitrogen atoms and the oxidn. state of the metal play a subordinate role. The most active bromo[1,3-diethyl-4,5-bis(2-fluorophenyl)-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) (5d) was distinctly more active than cisplatin. All complexes caused thioredoxin reductase (TrxR) inhibition (EC50 = 374-1505 nM) distinctly lower than Auranofin (EC50 = 18.6 nM) excluding this enzyme as main target. Because of the low nuclear content, a participation of DNA interaction on the mode of action is very unlikely. The missing ER binding and the missing correlation of growth inhibition and inactivation of COX enzymes exclude these targets, too.
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    Liu, W.; Bensdorf, K.; Hagenbach, A.; Abram, U.; Niu, B.; Mariappan, A.; Gust, R. Synthesis and biological studies of silver N-heterocyclic carbene complexes derived from 4,5-diarylimidazole. Eur. J. Med. Chem. 2011, 46, 5927– 5934,  DOI: 10.1016/j.ejmech.2011.10.002
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    23
    Synthesis and biological studies of silver N-heterocyclic carbene complexes derived from 4,5-diarylimidazole
    Liu, Wukun; Bensdorf, Kerstin; Hagenbach, Adelheid; Abram, Ulrich; Niu, Ben; Mariappan, Aruljothi; Gust, Ronald
    European Journal of Medicinal Chemistry (2011), 46 (12), 5927-5934CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A novel class of Ag N-heterocyclic carbene complexes, 4,5-(RC6H4)2-1-Et-3-R'C3N2AgX (5: X = Br, R' = Et, R = 2-F (a), 3-F (b), 4-F (c), 4-MeO (d), 4-OH (e); X = Cl, R' = PhCH2, R = 4-F (f)) was synthesized in 51% to 81% yield by reacting Ag(I) oxide with the appropriate 4,5-diarylimidazolium halide. The complexes were characterized using NMR and IR spectroscopy. The structure was confirmed on the example of bromo[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]silver(I) (5c) by crystal structure anal. The complexes are arranged in the crystal in dimeric units. Each metal binds one NHC and two bridging bromides. Pharmacol. studies revealed that all Ag complexes possessed growth inhibitory effects against breast cancer (MCF-7 and MDA-MB-231) as well as colon carcinoma (HT-29) cells. The most active compd. 5c was slightly less active against MCF-7 cells, more active against MDA-MB-231 cells and comparable active as cisplatin against HT-29 cells. Further pharmacol. studies were performed with selected compds. on estrogen receptor (ER) binding, DNA intercalation, cyclooxygenase (COX) inhibition and antibacterial activity. The complexes were only marginally active at the DNA, ER and the COX enzymes, so these targets can be excluded to be involved in the mode of action. However, the growth of bacteria was significantly inhibited by 5c and 5f and opens a new application of this complex type.
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    Meyer, A.; Oehninger, L.; Geldmacher, Y.; Alborzinia, H.; Wolfl, S.; Sheldrick, W. S.; Ott, I. Gold(I) N-heterocyclic carbene complexes with naphthalimide ligands as combined thioredoxin reductase inhibitors and DNA intercalators. ChemMedChem 2014, 9, 1794– 1800,  DOI: 10.1002/cmdc.201402049
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    Gold(I) N-Heterocyclic Carbene Complexes with Naphthalimide Ligands as Combined Thioredoxin Reductase Inhibitors and DNA Intercalators
    Meyer, Andreas; Oehninger, Luciano; Geldmacher, Yvonne; Alborzinia, Hamed; Woelfl, Stefan; Sheldrick, William S.; Ott, Ingo
    ChemMedChem (2014), 9 (8), 1794-1800CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Organometallic conjugates consisting of a gold(I) N-heterocyclic carbene (NHC) moiety and a naphthalimide were prepd. and investigated as cytotoxic agents that interact with both DNA and the disulfide reductase enzyme thioredoxin reductase (TrxR). The complexes were potent DNA intercalators related to their naphthalimide partial structure, inhibited TrxR as a consequence of the incorporation of the gold(I) moiety, and triggered efficient cytotoxic effects in MCF-7 breast and HT-29 colon adenocarcinoma cells. Strong effects on tumor cell metab. were noted for the most cytotoxic complex, chlorido[1-(3'-(4''-ethylthio-1'',8''-naphthalimid-N''-yl))-propyl-3-methyl-imidazol-2-ylidene]gold(I) (4 d). In conclusion, the conjugation of naphthalimides with gold(I) NHC moieties provided a useful strategy for the design of bioorganometallic anticancer agents with multiple modes of action.
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    Zou, T.; Lum, C. T.; Chui, S. S.; Che, C. M. Gold(III) complexes containing N-heterocyclic carbene ligands: thiol “switch-on” fluorescent probes and anti-cancer agents. Angew. Chem., Int. Ed. 2013, 52, 2930– 2933,  DOI: 10.1002/anie.201209787
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    Gold(III) Complexes Containing N-Heterocyclic Carbene Ligands: Thiol "Switch-on" Fluorescent Probes and Anti-Cancer Agents
    Zou, Taotao; Lum, Ching Tung; Chui, Stephen Sin-Yin; Che, Chi-Ming
    Angewandte Chemie, International Edition (2013), 52 (10), 2930-2933CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A class of Au(III) complexes bearing N-heterocyclic carbene and 2,6-bis(imidazol-2-yl)pyridine or 2,6-bis(benzimidazol-2-yl)pyridine ligands have been developed. These Au(III)-NHC complexes are sensitive towards thiols, which leads to release of fluorescent ligand, and thus can serve as a switch-on probe for thiols in biol. systems. The Au(III) complexes can also suppress tumor growth in mice bearing HeLa xenografts. These Au(III) complexes could be a promising scaffold for the future development of novel switch-on probes and anti-cancer agents.
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    Ott, I. Metal N-heterocyclic carbene complexes in medicinal chemistry. Adv. Inorg. Chem. 2020, 75, 121– 148,  DOI: 10.1016/bs.adioch.2019.10.008
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    Liu, W.; Gust, R. Metal N-heterocyclic carbene complexes as potential antitumor metallodrugs. Chem. Soc. Rev. 2013, 42, 755– 773,  DOI: 10.1039/C2CS35314H
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    Metal N-heterocyclic carbene complexes as potential antitumor metallodrugs
    Liu, Wukun; Gust, Ronald
    Chemical Society Reviews (2013), 42 (2), 755-773CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. The discovery of cisplatin's antitumor activity in 1969 prompted the search for novel metal-contg. complexes as potential anticancer drugs. Among these novel complexes, metal N-heterocyclic carbene (NHC) complexes have recently gained considerable attention because they perfectly fit prerequisites for efficient drug design and fast optimization. Moreover, most of them have shown higher cytotoxicity than cisplatin. This review describes the advances that have been achieved in using transition metal (Ag, Au, Pt, Pd, Cu, Ni, and Ru) complexes contg. NHC ligands as antitumor agents. Their modes of action at the cellular lever are further discussed. All these initial achievements clearly demonstrate the great potential of metal-NHC complexes as antitumor agents.
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  28. 28
    Hickey, J. L.; Ruhayel, R. A.; Barnard, P. J.; Baker, M. V.; Berners-Price, S. J.; Filipovska, A. Mitochondria-targeted chemotherapeutics: the rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols. J. Am. Chem. Soc. 2008, 130, 12570– 12571,  DOI: 10.1021/ja804027j
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    28
    Mitochondria-Targeted Chemotherapeutics: The Rational Design of Gold(I) N-Heterocyclic Carbene Complexes That Are Selectively Toxic to Cancer Cells and Target Protein Selenols in Preference to Thiols
    Hickey, James L.; Ruhayel, Rasha A.; Barnard, Peter J.; Baker, Murray V.; Berners-Price, Susan J.; Filipovska, Aleksandra
    Journal of the American Chemical Society (2008), 130 (38), 12570-12571CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A family of lipophilic, cationic Au(I) complexes of N-heterocyclic carbenes (NHCs) have been designed as new mitochondria-targeted antitumor agents that combine both selective mitochondrial accumulation and selective thioredoxin reductase inhibition properties within a single mol. Two-step ligand exchange reactions with cysteine (Cys) and selenocysteine (Sec) occur with release of the NHC ligands. At physiol. pH the rate consts. for the reactions with Sec are 20- to 80-fold higher than those with Cys. The complexes are selectively toxic to two highly tumorigenic breast cancer cell lines and not to normal breast cells, and the degree of selectivity and potency are optimized by modification of the substituent on the simple imidazolium salt precursor. The lead compd. is shown to accumulate in mitochondria of cancer cells, to cause cell death through a mitochondrial apoptotic pathway and to inhibit the activity of thioredoxin reductase (TrxR) but not the closely related and Se-free enzyme glutathione reductase.
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    Liu, W.; Gust, R. Update on metal N-heterocyclic carbene complexes as potential anti-tumor metallodrugs. Coord. Chem. Rev. 2016, 329, 191– 213,  DOI: 10.1016/j.ccr.2016.09.004
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    Update on metal N-heterocyclic carbene complexes as potential anti-tumor metallodrugs
    Liu, Wukun; Gust, Ronald
    Coordination Chemistry Reviews (2016), 329 (), 191-213CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
    The clin. success of platinum-based chemotherapeutic agents was of enormous impact on the discovery of novel metal N-heterocyclic carbene (NHC) complexes as potential anti-cancer drugs. During the last years, the research on cytotoxic transition metal (e.g. Ag, Au, Pt, Pd, Cu, Hg, Ru, Os, Rh and Ir) NHC complexes was successful and the results are remarkable. In this review, we provide an update on the recent advances in this direction, which reflects new discoveries since the publication of our previous review. The anti-tumor properties along with the mechanisms of action for these complexes as well as possible structure-activity relationships are discussed.
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    Schmidt, C.; Albrecht, L.; Balasupramaniam, S.; Misgeld, R.; Karge, B.; Bronstrup, M.; Prokop, A.; Baumann, K.; Reichl, S.; Ott, I. A gold(I) biscarbene complex with improved activity as a TrxR inhibitor and cytotoxic drug: comparative studies with different gold metallodrugs. Metallomics 2019, 11, 533– 545,  DOI: 10.1039/C8MT00306H
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    A gold(I) biscarbene complex with improved activity as a TrxR inhibitor and cytotoxic drug: comparative studies with different gold metallodrugs
    Schmidt, Claudia; Albrecht, Lucia; Balasupramaniam, Shantheya; Misgeld, Rainer; Karge, Bianka; Broenstrup, Mark; Prokop, Aram; Baumann, Knut; Reichl, Stephan; Ott, Ingo
    Metallomics (2019), 11 (3), 533-545CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
    Gold complexes with N-heterocyclic carbene (NHC) ligands have been attracting major attention in medicinal inorg. chem. based on their favorable antiproliferative effects and the structural versatility of the coordinated NHC ligands. Here we present a novel complex of the type (NHC)2Au+, which represents a substantially improved and selective TrxR inhibitor compared to close structural analogs. The complex is highly stable in various solns. over 96 h, however, comparative cellular uptake studies indicate metabolic transformations inside cells over time. A portfolio of other gold complexes (e.g. Auranofin) has been used as refs. in key biol. assays, showing that the novel (NHC)2Au+ complex exhibits substantially lower protein binding in combination with a strongly enhanced cytotoxic activity.
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    Baker, M. V.; Barnard, P. J.; Brayshaw, S. K.; Hickey, J. L.; Skelton, B. W.; White, A. H. Synthetic, structural and spectroscopic studies of (pseudo)halo(1,3-di-tert-butylimidazol-2-ylidine)gold complexes. Dalton Trans. 2005, 1, 37– 43,  DOI: 10.1039/b412540a
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    Messori, L.; Marchetti, L.; Massai, L.; Scaletti, F.; Guerri, A.; Landini, I.; Nobili, S.; Perrone, G.; Mini, E.; Leoni, P.; Pasquali, M.; Gabbiani, C. Chemistry and biology of two novel gold(I) carbene complexes as prospective anticancer agents. Inorg. Chem. 2014, 53, 2396– 2403,  DOI: 10.1021/ic401731a
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    Chemistry and Biology of Two Novel Gold(I) Carbene Complexes as Prospective Anticancer Agents
    Messori, Luigi; Marchetti, Lorella; Massai, Lara; Scaletti, Federica; Guerri, Annalisa; Landini, Ida; Nobili, Stefania; Perrone, Gabriele; Mini, Enrico; Leoni, Piero; Pasquali, Marco; Gabbiani, Chiara
    Inorganic Chemistry (2014), 53 (5), 2396-2403CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    Two novel gold carbene compds., namely, chloro (1-butyl-3-methyl-imidazole-2-ylidene) gold(I) (1) and bis(1-butyl-3-methyl-imidazole-2-ylidene) gold(I) (2), were prepd. and characterized as prospective anticancer drug candidates. These compds. consist of a gold(I) center linearly coordinated either to one N-heterocyclic carbene (NHC) and one chloride ligand (1) or to two identical NHC ligands (2). Crystal structures were solved for both compds., the resulting structural data being in good agreement with expectations. We wondered whether the presence of two tight carbene ligands in 2 might lead to biol. properties distinct from those of the monocarbene complex 1. Notably, in spite of their appreciable structural differences, these two compds. manifested similarly potent cytotoxic actions in vitro when challenged against A2780 human ovarian carcinoma cells. In addn., both were able to overcome resistance to cisplatin in the A2780R line. Soln. studies revealed that these gold carbene complexes are highly stable in aq. buffers at physiol. pH. Their reactivity with proteins was explored: no adduct formation was detected even upon a long incubation with the model proteins cytochrome c and lysozyme; in contrast, both compds. were able to metalate, to a large extent, the copper chaperone Atox-1, bearing a characteristic CXXC motif. The precise nature of the resulting gold-Atox-1 adducts was elucidated through ESI-MS anal. On the basis of these findings, it is proposed that the investigated gold(I) carbene compds. are promising antiproliferative agents warranting a wider pharmacol. evaluation. Most likely these gold compds. produce their potent biol. effects through selective metalation and impairment of a few crucial cellular proteins.
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    Marzo, T.; Cirri, D.; Gabbiani, C.; Gamberi, T.; Magherini, F.; Pratesi, A.; Guerri, A.; Biver, T.; Binacchi, F.; Stefanini, M.; Arcangeli, A.; Messori, L. Auranofin, Et3PAuCl, and Et3PAuI are highly cytotoxic on colorectal cancer cells: a chemical and biological study. ACS Med. Chem. Lett. 2017, 8, 997– 1001,  DOI: 10.1021/acsmedchemlett.7b00162
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    Auranofin, Et3PAuCl, and Et3PAuI Are Highly Cytotoxic on Colorectal Cancer Cells: A Chemical and Biological Study
    Marzo, Tiziano; Cirri, Damiano; Gabbiani, Chiara; Gamberi, Tania; Magherini, Francesca; Pratesi, Alessandro; Guerri, Annalisa; Biver, Tarita; Binacchi, Francesca; Stefanini, Matteo; Arcangeli, Annarosa; Messori, Luigi
    ACS Medicinal Chemistry Letters (2017), 8 (10), 997-1001CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
    The soln. behavior of auranofin, Et3PAuCl and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward representative colorectal cancer cell lines were found to be strong and similar in the three cases and a good correlation could be established between the cytotoxicity and the ability to inhibit thioredoxin reductase; remarkably, in vivo acute toxicity expts. for Et3PAuI confirmed that, similarly to auranofin, this drug is well tolerated in a murine model. Overall, a very similar profile emerges for Et3PAuI and Et3PAuCl, which retain the potent cytotoxic effects of auranofin while showing some peculiar features. These results demonstrate that the presence of the thiosugar moiety is not mandatory for the pharmacol. action, suggesting that the tuning of some relevant chem. properties such as lipophilicity could be exploited to improve bioavailability, with no loss of the pharmacol. effects.
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    Karaca, O.; Scalcon, V.; Meier-Menches, S. M.; Bonsignore, R.; Brouwer, J.; Tonolo, F.; Folda, A.; Rigobello, M. P.; Kuhn, F. E.; Casini, A. Characterization of hydrophilic gold(I) N-heterocyclic carbene (NHC) complexes as potent TrxR inhibitors using biochemical and mass spectrometric approaches. Inorg. Chem. 2017, 56, 14237– 14250,  DOI: 10.1021/acs.inorgchem.7b02345
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    Characterization of Hydrophilic Gold(I) N-Heterocyclic Carbene (NHC) Complexes as Potent TrxR Inhibitors Using Biochemical and Mass Spectrometric Approaches
    Karaca, Oezden; Scalcon, Valeria; Meier-Menches, Samuel M.; Bonsignore, Riccardo; Brouwer, Jurriaan M. J. L.; Tonolo, Federica; Folda, Alessandra; Rigobello, Maria Pia; Kuehn, Fritz E.; Casini, Angela
    Inorganic Chemistry (2017), 56 (22), 14237-14250CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
    The authors report on the synthesis of a series of mono- and dinuclear gold(I) complexes exhibiting sulfonated bis(NHC) ligands and novel hydroxylated mono(NHC) Au(I) compds., which were also examd. for their biol. activities. Initial cell viability assays show strong antiproliferative activities of the hydroxylated mono(NHC) gold compds. (8 > 9 > 10) against 2008 human ovarian cancer cells even after 1 h incubation. To gain insight into the mechanism of biol. action of the gold compds., their effect on the pivotal cellular target seleno-enzyme thioredoxin reductase (TrxR), involved in the maintenance of intracellular redox balance, was investigated in depth. The compds.' inhibitory effects on TrxR and glutathione reductase (GR) were studied comparatively, using either the pure proteins or cancer cell exts. The results show a strong and selective inhibitory effect of TrxR, specifically for the hydroxyl-functionalized NHC gold(I) complexes (8-10). Valuable information on the gold compds.' mol. reactivity with TrxR was gained using the BIAM (biotin-conjugated iodoacetamide) assay and performing competition expts. by mass spectrometry (MS). In good agreement, both techniques suggest the binding affinity of the mono(NHC) Au(I) complexes toward selenols and thiols. Notably, for the first time, bis-carbene formation from mono-carbenes in buffered soln. could be obsd. by MS, which may provide new insights into the speciation mechanisms of bioactive Au(I) NHC complexes. Furthermore, the compds.' interactions with another relevant in cellulo target, namely telomeric G-quadruplex DNA-a higher-order DNA structure playing key roles in telomere function-was investigated by FRET melting assays. The lack of interactions with this type of nucleic acid secondary structure support the idea of selective targeting of the hydrophilic Au(I) NHC compds. toward proteins such as TrxR.
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    Mirzayans, R.; Andrais, B.; Murray, D. Do Multiwell Plate High Throughput Assays Measure Loss of Cell Viability Following Exposure to Genotoxic Agents?. Int. J. Mol. Sci. 2017, 18, 1679,  DOI: 10.3390/ijms18081679
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    Do multiwell plate high throughput assays measure loss of cell viability following exposure to genotoxic agents?
    Mirzayans, Razmik; Andrais, Bonnie; Murray, David
    International Journal of Molecular Sciences (2017), 18 (8), 1679/1-1679/10CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    Cell-based assays in multiwell plates are widely used for radiosensitivity and chemosensitivity assessment with different mammalian cell types. Despite their relative ease of performance, such assays lack specificity as they do not distinguish between the cytostatic (reversible/sustained growth arrest) and cytotoxic (loss of viability) effects of genotoxic agents. We recently reported studies with solid tumor-derived cell lines demonstrating that radiosensitivity as measured by multiwell plate colorimetric (e.g., XTT) and fluorimetric (e.g., CellTiter-Blue) assays reflects growth arrest but not loss of viability. Herein we report similar observations with cancer cell lines expressing wild-type p53 (A549 lung carcinoma) or mutant p53 (MDA-MB-231 breast carcinoma) after treatment with the chemotherapeutic drug cisplatin. Importantly, we show that treatment of cancer cells with concns. of cisplatin that result in 50% effect (i.e., IC50) in multiwell plate assays trigger the emergence of growth arrested cells that exhibit highly enlarged morphol., remain viable and adherent to the culture dish, and metabolize the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) to its formazan deriv. The emergence of markedly enlarged viable cells complicates the interpretation of chemosensitivity data obtained with multiwell plate high throughput assays. Relying solely on IC50 values could be misleading.
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    Monteiro-Riviere, N. A.; Inman, A. O.; Zhang, L. W. Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line. Toxicol. Appl. Pharmacol. 2009, 234, 222– 235,  DOI: 10.1016/j.taap.2008.09.030
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    Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line
    Monteiro-Riviere, N. A.; Inman, A. O.; Zhang, L. W.
    Toxicology and Applied Pharmacology (2009), 234 (2), 222-235CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)
    Single-walled carbon nanotubes (SWCNT), fullerenes (C60), carbon black (CB), nC60, and quantum dots (QD) have been studied in vitro to det. their toxicity in a no. of cell types. Here, the authors report that classical dye-based assays such as MTT and neutral red (NR) that det. cell viability produce invalid results with some NM (nanomaterials) due to NM/dye interactions and/or NM adsorption of the dye/dye products. In this study, human epidermal keratinocytes (HEK) were exposed in vitro to CB, SWCNT, C60, nC60, and QD to assess viability with calcein AM (CAM), Live/Dead (LD), NR, MTT, Celltiter 96 Aq. One (96 AQ), alamar Blue (aB), Celltiter-Blue (CTB), CytoTox One (CTO), and flow cytometry. In addn., trypan blue (TB) was quantitated by light microscopy. Assay linearity (R2 value) was detd. with HEK plated at concns. from 0 to 25,000 cells per well in 96-well plates. HEK were treated with serial dilns. of each NM for 24 h and assessed with each of the viability assays. TB, CAM and LD assays, which depend on direct staining of living and/or dead cells, were difficult to interpret due to phys. interference of the NM with cells. Results of the dye-based assays varied a great deal, depending on the interactions of the dye/dye product with the carbon nanomaterials (CNM). Results show the optimal high throughput assay for use with carbon and noncarbon NM was 96 AQ. This study shows that, unlike small mols., CNM interact with assay markers to cause variable results with classical toxicol. assays and may not be suitable for assessing nanoparticle cytotoxicity. Therefore, more than one assay may be required when detg. nanoparticle toxicity for risk assessment.
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    Ott, I.; Qian, X.; Xu, Y.; Vlecken, D. H.; Marques, I. J.; Kubutat, D.; Will, J.; Sheldrick, W. S.; Jesse, P.; Prokop, A.; Bagowski, C. P. A gold(I) phosphine complex containing a naphthalimide ligand functions as a TrxR inhibiting antiproliferative agent and angiogenesis inhibitor. J. Med. Chem. 2009, 52, 763– 770,  DOI: 10.1021/jm8012135
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    A Gold(I) Phosphine Complex Containing Naphthalimide Ligand Functions as a TrxR Inhibiting Antiproliferative Agent and Angiogenesis Inhibitor
    Ott, Ingo; Qian, Xuhong; Xu, Yufang; Vlecken, Danielle H. W.; Marques, Ines J.; Kubutat, Dominic; Will, Joanna; Sheldrick, William S.; Jesse, Patrick; Prokop, Aram; Bagowski, Christoph P.
    Journal of Medicinal Chemistry (2009), 52 (3), 763-770CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The novel luminescent gold(I) complex [N-(N',N'-dimethylaminoethyl)-1,8-naphthalimide-4-sulfide](triethylphosphine)gold(I) was prepd. and investigated for its primary biol. properties. Cell culture expts. revealed strong antiproliferative effects and induction of apoptosis via mitochondrial pathways. Biodistribution studies by fluorescence microscopy and at. absorption spectroscopy showed the uptake into cell organelles, an accumulation in the nuclei of tumor cells, and a homogeneous distribution in zebrafish embryos. In vivo monitoring of vascularization in developing zebrafish embryos revealed a significant anti-angiogenic potency of the complex. Mechanistic expts. indicated that the inhibition of thioredoxin reductase (based on the covalent binding of a gold triethylphosphine fragment) might be involved in the pharmacodynamic behavior of this novel gold species.
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    Bian, M.; Fan, R.; Zhao, S.; Liu, W. Targeting the thioredoxin system as a strategy for cancer therapy. J. Med. Chem. 2019, 62, 7309– 7321,  DOI: 10.1021/acs.jmedchem.8b01595
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    Targeting the thioredoxin system as a strategy for cancer therapy
    Bian, Mianli; Fan, Rong; Zhao, Sai; Liu, Wukun
    Journal of Medicinal Chemistry (2019), 62 (16), 7309-7321CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. Thioredoxin reductase (TrxR) participates in the regulation of redox reactions in organisms. It works mainly via its substrate mol., thioredoxin, to maintain the redox balance and regulate signal transduction, which controls cell proliferation, differentiation, death, and other important physiol. processes. In recent years, increasing evidence has shown that the overactivation of TrxR is related to the development of tumors. The exploration of TrxR-targeted antitumor drugs has attracted wide attention and is expected to provide new therapies for cancer treatment. In this perspective, we highlight the specific relationship between TrxR and apoptotic signaling pathways. The cytoplasm and mitochondria both contain TrxR, resulting in the activation of apoptosis. TrxR activity influences reactive oxygen species (ROS) and further regulates the inflammatory signaling pathway. In addn., we discuss representative TrxR inhibitors with anticancer activity and analyze the challenges in developing TrxR inhibitors as anticancer drugs.
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    Zhang, J.; Zhang, B.; Li, X.; Han, X.; Liu, R.; Fang, J. Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: an update. Med. Res. Rev. 2019, 39, 5– 39,  DOI: 10.1002/med.21507
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    Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update
    Zhang, Junmin; Zhang, Baoxin; Li, Xinming; Han, Xiao; Liu, Ruijuan; Fang, Jianguo
    Medicinal Research Reviews (2019), 39 (1), 5-39CODEN: MRREDD; ISSN:0198-6325. (John Wiley & Sons, Inc.)
    A review. Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small mol. modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small mol. inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of mols. were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive ref. in the medicinal chem., and have a broad audience across multiple disciplines.
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    Zhang, B.; Liu, Y.; Li, X.; Xu, J.; Fang, J. Small molecules to target the selenoprotein thioredoxin reductase. Chem. - Asian J. 2018, 13, 3593– 3600,  DOI: 10.1002/asia.201801136
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    Small Molecules to Target the Selenoprotein Thioredoxin Reductase
    Zhang, Baoxin; Liu, Yuxin; Li, Xinming; Xu, Jianqiang; Fang, Jianguo
    Chemistry - An Asian Journal (2018), 13 (23), 3593-3600CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. The selenoprotein thioredoxin reductase (TrxR) enzymes are the only identified proteins that maintain thioredoxin (Trx) proteins in a reduced state under physiol. conditions, and consequently play a pivotal role in the regulation of various cellular redox signaling pathways involved in cell differentiation, growth, and death. The elevated expression of TrxR enzymes has been obsd. in different types of cancer cells, and this overexpression is of pathol. significance in maintaining tumor phenotypes, such as uncontrolled proliferation and resistance to apoptosis. Herein, the authors discuss recent advances in the study of TrxR, including classic assays of TrxR, the emerging chem. tools of TrxR, and small mols. that target TrxR as potential anticancer agents.
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    Huang, K. B.; Wang, F. Y.; Tang, X. M.; Feng, H. W.; Chen, Z. F.; Liu, Y. C.; Liu, Y. N.; Liang, H. Organometallic gold(III) complexes similar to tetrahydroisoquinoline induce ER-stress-mediated apoptosis and pro-death autophagy in A549 cancer cells. J. Med. Chem. 2018, 61, 3478– 3490,  DOI: 10.1021/acs.jmedchem.7b01694
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    Organometallic Gold(III) complexes similar to tetrahydroisoquinoline induce ER-stress-mediated apoptosis and pro-death autophagy in A549 cancer cells
    Huang, Ke-Bin; Wang, Feng-Yang; Tang, Xiao-Ming; Feng, Hai-Wen; Chen, Zhen-Feng; Liu, Yan-Cheng; Liu, You-Nian; Liang, Hong
    Journal of Medicinal Chemistry (2018), 61 (8), 3478-3490CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Gold(III) cyclometalated benzeneethanamine chelate complexes exhibit high cytotoxic activity towards lung cancer cells, causing ER-controlled apoptosis and autophagy, exhibiting less toxicity compared to cisplatin. Agents inducing both apoptosis and autophagic death can be effective chemotherapeutic drugs. In our present work, we synthesized two organometallic gold(III) complexes harboring C-N ligands that structurally resemble tetrahydroisoquinoline (THIQ): Cyc-Au-1 (AuL1Cl2, HL1 = 3,4-dimethoxyphenethylamine) and Cyc-Au-2 (AuL2Cl2, HL2 = 1,3-benzodioxole-5-ethanamine). In screening their in vitro activity, we found both gold complexes exhibited lower toxicity, lower resistance factors, and better anticancer activity than those of cisplatin. The organometallic gold(III) complexes accumulate in mitochondria and induce elevated ROS and an ER stress response through mitochondrial dysfunction. These effects ultimately result in simultaneous apoptosis and autophagy. Importantly, compared to cisplatin, Cyc-Au-2 exhibits lower toxicity and better anticancer activity in a murine tumor model. To the best of our knowledge, Cyc-Au-2 is the first organometallic Au(III) compd. that induces apoptosis and autophagic death. On the basis of our results, we believe Cyc-Au-2 to be a promising anticancer agent or lead compd. for further anticancer drug development.
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    Bian, M.; Sun, Y.; Liu, Y.; Xu, Z.; Fan, R.; Liu, Z.; Liu, W. A gold(I) complex containing an oleanolic acid derivative as a potential anti-ovarian cancer agent via inhibiting TrxR and activating ROS-mediated ERS. Chem. - Eur. J. 2020, 26, 7092– 7108,  DOI: 10.1002/chem.202000045
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    A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti-Ovarian-Cancer Agent by Inhibiting TrxR and Activating ROS-Mediated ERS
    Bian, Mianli; Sun, Ying; Liu, Yuanhao; Xu, Zhongren; Fan, Rong; Liu, Ziwen; Liu, Wukun
    Chemistry - A European Journal (2020), 26 (31), 7092-7108CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Many cancer cells critically rely on antioxidant systems for cell survival and are vulnerable to further oxidative impairment triggered by agents generating reactive oxygen species (ROS). Therefore, the classical design and development of inhibitors that target antioxidant defense enzymes such as thioredoxin reductase (TrxR) can be a promising anticancer strategy. Herein, it is shown that a gold(I) complex contg. an oleanolic acid deriv. (4 b) induces apoptosis of ovarian cancer A2780 cells by activating endoplasmic reticulum stress (ERS). It can inhibit TrxR enzyme activity to elevate ROS, mediate ERS and mitochondrial dysfunction, and finally leads to cell cycle arrest and apoptosis of A2780 cells. Notably, this complex inhibits A2780 xenograft tumor growth accompanied by increased ERS level and decreased TrxR activity in tumor tissues.
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    Wang, K.; Zhu, C.; He, Y.; Zhang, Z.; Zhou, W.; Muhammad, N.; Guo, Y.; Wang, X.; Guo, Z. Restraining cancer cells by dual metabolic inhibition with a mitochondrion-targeted platinum(II) complex. Angew. Chem., Int. Ed. 2019, 58, 4638– 4643,  DOI: 10.1002/anie.201900387
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    Restraining Cancer Cells by Dual Metabolic Inhibition with a Mitochondrion-Targeted Platinum(II) Complex
    Wang, Kun; Zhu, Chengcheng; He, Yafeng; Zhang, Zhenqin; Zhou, Wen; Muhammad, Nafees; Guo, Yan; Wang, Xiaoyong; Guo, Zijian
    Angewandte Chemie, International Edition (2019), 58 (14), 4638-4643CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Cancer cells usually adapt metabolic phenotypes to chemotherapeutics. A defensive strategy against this flexibility is to modulate signaling pathways relevant to cancer bioenergetics. A triphenylphosphonium-modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabs. of cancer cells. TTP exhibited enhanced cytotoxicity against cisplatin-insensitive human ovarian cancer cells in a caspase-3-independent manner and showed preferential inhibition to mitochondrial TrxR. The morphol. and function of mitochondria were severely damaged, and the levels of mitochondrial and cellular reactive oxygen species were decreased. As a result, TTP exerted strong inhibition to both mitochondrial and glycolytic bioenergetics, thus inducing cancer cells to enter a hypometabolic state.
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    Kalyanaraman, B.; Darley-Usmar, V.; Davies, K. J.; Dennery, P. A.; Forman, H. J.; Grisham, M. B.; Mann, G. E.; Moore, K.; Roberts, L. J., 2nd; Ischiropoulos, H. Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radical Biol. Med. 2012, 52, 1– 6,  DOI: 10.1016/j.freeradbiomed.2011.09.030
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    Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations
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    Free Radical Biology & Medicine (2012), 52 (1), 1-6CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
    The purpose of this position paper is to present a crit. anal. of the challenges and limitations of the most widely used fluorescent probes for detecting and measuring reactive oxygen and nitrogen species. Where feasible, the authors have made recommendations for the use of alternate probes and appropriate anal. techniques that measure the specific products formed from the reactions between fluorescent probes and reactive oxygen and nitrogen species. The authors have proposed guidelines that will help present and future researchers with regard to the optimal use of selected fluorescent probes and interpretation of results.
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    Wu, K. J.; Zhong, H. J.; Yang, G.; Wu, C.; Huang, J. M.; Li, G.; Ma, D. L.; Leung, C. H. Small molecule Pin1 inhibitor blocking NF-kappaB signaling in prostate cancer cells. Chem. - Asian J. 2018, 13, 275– 279,  DOI: 10.1002/asia.201701216
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    Small Molecule Pin1 Inhibitor Blocking NF-κB Signaling in Prostate Cancer Cells
    Wu, Ke-Jia; Zhong, Hai-Jing; Yang, Guanjun; Wu, Chun; Huang, Jie-Min; Li, Guodong; Ma, Dik-Lung; Leung, Chung-Hang
    Chemistry - An Asian Journal (2018), 13 (3), 275-279CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Prolyl-isomerase 1 (Pin1) is a conserved enzyme that regulates cell processes such as cell cycle progression, transcriptional regulation, and apoptosis. However, overexpression of Pin1 is correlated with a higher probability of prostate tumor recurrence. The authors utilized a mol. docking technique to identify Pin1 inhibitors from a database of natural product and natural product-like compds. The action of the hit compds. against Pin1 activity was studied using multiple methods, including a fluorometric enzymic assay, co-immunopptn., western blotting, cell thermal shiftm, and other techniques. The authors have identified compd. 1 (I) as a natural-product-like inhibitor of Pin1 activity via structure-based virtual screening and showed that compd. 1 could target Pin1 and disrupt the interaction between Pin1 and the p65 subunit of NF-κB in cells. Furthermore, compd. 1 reduced nuclear p65 (Thr 254) phosphorylation and attenuated NF-κB activity in cells. Finally, compd. 1 induced apoptosis in prostate cancer cells. Compd. 1 represents a natural product-like Pin1 inhibitor that acts via targeting the Pin1-NF-κB interaction.
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    Wu, K. J.; Zhong, H. J.; Li, G.; Liu, C.; Wang, H. D.; Ma, D. L.; Leung, C. H. Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing. Eur. J. Med. Chem. 2018, 143, 1021– 1027,  DOI: 10.1016/j.ejmech.2017.11.101
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    Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing
    Wu, Ke-Jia; Zhong, Hai-Jing; Li, Guodong; Liu, Chenfu; Wang, Hui-Min David; Ma, Dik-Lung; Leung, Chung-Hang
    European Journal of Medicinal Chemistry (2018), 143 (), 1021-1027CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    NEDD8-activating enzyme (NAE) is an essential player of the NEDD8 conjugation pathway that regulates protein degrdn. Meanwhile, drug repurposing is a cost-efficient strategy to identify new therapeutic uses for existing scaffolds. In this report, mitoxantrone (1) was repurposed as an inhibitor of NAE by virtual screening of an FDA-approved drug database. Compd. 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity and was competitive with ATP. Furthermore, compd. 1 induced apoptosis of colorectal adenocarcinoma cancer cells through inhibiting the degrdn. of the neddylation substrate p53.
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    Nishanth, R. P.; Jyotsna, R. G.; Schlager, J. J.; Hussain, S. M.; Reddanna, P. Inflammatory responses of RAW 264.7 macrophages upon exposure to nanoparticles: role of ROS-NFkappaB signaling pathway. Nanotoxicology 2011, 5, 502– 516,  DOI: 10.3109/17435390.2010.541604
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    Inflammatory responses of RAW 264.7 macrophages upon exposure to nanoparticles: role of ROS-NFκB signaling pathway
    Nishanth, Reddy P.; Jyotsna, Radhika G.; Schlager, John J.; Hussain, Saber M.; Reddanna, Pallu
    Nanotoxicology (2011), 5 (4), 502-516CODEN: NANOGK; ISSN:1743-5404. (Informa Healthcare)
    Recent advances in particle-forming chemistries used for developing nanotechnol. has not only widened novel applications for nanoscale materials but also has provided significant concern regarding their biol. effects. The present study investigates the inflammatory responses of RAW 264.7 mouse macrophages exposed to nanoparticles (NPs, 5 μg/mL) of varied sizes including silver (Ag), aluminum (Al), carbon black (CB), carbon coated silver (CAg) and gold (Au). A significant increase in IL-6, reactive oxygen species (ROS) generation, nuclear translocation of nuclear factor-kappa B (NF-κB), induction of cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-α) expression was obsd. in macrophages with max. response found in cells exposed to Ag NPs followed by Al, CB and CAg. These pro-inflammatory effects of NPs were dependent on size and duration of exposure and comparable to those induced by lipopolysaccharide (LPS), a known inflammatory mediator. Au NPs, on the other hand, induced small but significant inflammatory responses in macrophages upon prolonged exposure. These studies reveal that Ag NPs exhibit higher propensity in inducing inflammation, mediated by ROS and NF-κB signaling pathways and leading to the induction of COX-2, TNF-α and IL-6. However, no such prominent pro-inflammatory responses were obsd. with Au NPs, suggesting their bio-compatibility.
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    Hsu, C. C.; Lien, J. C.; Chang, C. W.; Chang, C. H.; Kuo, S. C.; Huang, T. F. Yuwen02f1 suppresses LPS-induced endotoxemia and adjuvant-induced arthritis primarily through blockade of ROS formation, NFkB and MAPK activation. Biochem. Pharmacol. 2013, 85, 385– 395,  DOI: 10.1016/j.bcp.2012.11.002
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    Yuwen02f1 suppresses LPS-induced endotoxemia and adjuvant-induced arthritis primarily through blockade of ROS formation, NFkB and MAPK activation
    Hsu, Chun-Chieh; Lien, Jin-Cherng; Chang, Chia-Wen; Chang, Chien-Hsin; Kuo, Sheng-Chu; Huang, Tur-Fu
    Biochemical Pharmacology (Amsterdam, Netherlands) (2013), 85 (3), 385-395CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
    Phagocytes release inflammatory mediators to defense harmful stimuli upon bacterial invasion, however, excessive inflammatory reaction leads to tissue damage and manifestation of pathol. states. Therefore, targeting on uncontrolled inflammation seems feasible to control numerous inflammation-assocd. diseases. Under the drug screening process of synthetic diphenylpyrazole derivs., we discovered compd. yuwen02f1 possesses anti-inflammatory effects in decreasing the release of pro-inflammatory cytokines including TNFα and IL-6, nitric oxide, reactive oxygen species (ROS) as well as inhibiting migration of LPS-stimulated phagocytes. In addn., we obsd. that the mol. mechanism of yuwen02f1-mediated anti-inflammation is assocd. with decreasing phosphorylation of MAPK mols. including ERK1/2, JNK and p38, and attenuating translocation of p47phox and p67phox to the cell membrane. Yuwen02f1 also reverses IκBα degrdn. and attenuates the expression of NFκB-related downstream inducible enzymes like iNOS and COX-2. Furthermore, we found that yuwen02f1 attenuates some pathol. syndromes of LPS-induced sepsis and adjuvant-induced arthritis in mice, as evidenced by decreasing the cytokine prodn., reversing thrombocytopenic syndrome, protecting the mice from tissue injury in septic mice, and attenuating paw edema in arthritic mice as well. These results suggest that yuwen02f1 is a potential anti-inflammatory agent for alleviating syndromes of acute and chronic inflammatory diseases as evidenced by attenuating the generation of cytokines and down-regulating the expression of iNOS and COX-2 through the blockade of ROS generation and NADPH oxidase, NFκB and MAPK activation pathways in LPS-stimulated phagocytes.
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    Huang, Q.; Zhan, L.; Cao, H.; Li, J.; Lyu, Y.; Guo, X.; Zhang, J.; Ji, L.; Ren, T.; An, J.; Liu, B.; Nie, Y.; Xing, J. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy 2016, 12, 999– 1014,  DOI: 10.1080/15548627.2016.1166318
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    Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways
    Huang, Qichao; Zhan, Lei; Cao, Haiyan; Li, Jibin; Lyu, Yinghua; Guo, Xu; Zhang, Jing; Ji, Lele; Ren, Tingting; An, Jiaze; Liu, Bingrong; Nie, Yongzhan; Xing, Jinliang
    Autophagy (2016), 12 (6), 999-1014CODEN: AUTOC9; ISSN:1554-8635. (Taylor & Francis Ltd.)
    Mitochondrial morphol. is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, esp. in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying mol. mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS prodn. and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degrdn., and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a crit. role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.
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    Fan, R.; Bian, M.; Hu, L.; Liu, W. A new rhodium(I) NHC complex inhibits TrxR: In vitro cytotoxicity and in vivo hepatocellular carcinoma suppression. Eur. J. Med. Chem. 2019, 183, 111721,  DOI: 10.1016/j.ejmech.2019.111721
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    A new rhodium(I) NHC complex inhibits TrxR: In vitro cytotoxicity and in vivo hepatocellular carcinoma suppression
    Fan, Rong; Bian, Mianli; Hu, Lihong; Liu, Wukun
    European Journal of Medicinal Chemistry (2019), 183 (), 111721CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    Thioredoxin reductase (TrxR) is often overexpressed in different types of cancer cells including hepatocellular carcinoma (HCC) cells and regarded as a target with great promise for anticancer drug research and development. Here, we have synthesized and characterized nine new designed rhodium(I) N-heterocyclic carbene (NHC) complexes. All of them were effective towards cancer cells, esp. complex 1e was more active than cisplatin and manifested strong antiproliferative activity against HCC cells. In vivo anticancer studies showed that 1e significantly repressed tumor growth in an HCC nude mouse model and ameliorated liver lesions in a chronic HCC model caused by CCl4. Notably, a mechanistic study revealed that 1e can strongly inhibit TrxR system both in vitro and in vivo. Furthermore, 1e promoted intracellular ROS accumulation, damaged mitochondrial membrane potential, promoted cancer cell apoptosis and blocked the cells in the G1 phase.
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    Huang, W.; Liu, Y.; Wang, J.; Yuan, X.; Jin, H. W.; Zhang, L. R.; Zhang, J. T.; Liu, Z. M.; Cui, J. R. Small-molecule compounds targeting the STAT3 DNA-binding domain suppress survival of cisplatin-resistant human ovarian cancer cells by inducing apoptosis. Eur. J. Med. Chem. 2018, 157, 887– 897,  DOI: 10.1016/j.ejmech.2018.08.037
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    Small-molecule compounds targeting the STAT3 DNA-binding domain suppress survival of cisplatin-resistant human ovarian cancer cells by inducing apoptosis
    Huang, Wei; Liu, Yuan; Wang, Jun; Yuan, Xia; Jin, Hong-Wei; Zhang, Liang-Ren; Zhang, Jian-Ting; Liu, Zhen-Ming; Cui, Jing-Rong
    European Journal of Medicinal Chemistry (2018), 157 (), 887-897CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    Constitutive activation of signal transducer and activator of transcription 3 (STAT3) plays important roles in oncogenic occurrence and transformation by regulating the expression of diverse downstream target genes important for tumor growth, metastasis, angiogenesis and immune evasion. Feasibility of targeting the DNA-binding domain (DBD) of STAT3 has been proven previously. With the aid of 3D shape- and electrostatic-based drug design, we identified a new STAT3 inhibitor, LC28, and its five analogs, based on the pharmacophore of a known STAT3 DBD inhibitor. Microscale thermophoresis assay shows that these compds. inhibits STAT3 binding to DNA with a Ki value of 0.74-8.87 μM. Furthermore, LC28 and its analogs suppress survival of cisplatin-resistant ovarian cancer cells by inhibiting STAT3 signaling and inducing apoptosis. Therefore, these compds. may serve as candidate compds. for further modification and development as anticancer therapeutics targeting the DBD of human STAT3 for treatment of cisplatin-resistant ovarian cancer.
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    Bian, M.; Chen, X.; Zhang, C.; Jin, H.; Wang, F.; Shao, J.; Chen, A.; Zhang, F.; Zheng, S. Magnesium isoglycyrrhizinate promotes the activated hepatic stellate cells apoptosis via endoplasmic reticulum stress and ameliorates fibrogenesis in vitro and in vivo. Biofactors 2017, 43, 836– 846,  DOI: 10.1002/biof.1390
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    Magnesium isoglycyrrhizinate promotes the activated hepatic stellate cells apoptosis via endoplasmic reticulum stress and ameliorates fibrogenesis in vitro and in vivo
    Bian, Mianli; Chen, Xingran; Zhang, Chenxi; Jin, Huanhuan; Wang, Feixia; Shao, Jiangjuan; Chen, Anping; Zhang, Feng; Zheng, Shizhong
    BioFactors (2017), 43 (6), 836-846CODEN: BIFAEU; ISSN:1872-8081. (Wiley-Blackwell)
    Varied pathogenetic elements have been touched upon the liver fibrosis, including inflammatory, stress, apoptosis and unfolded proteins aggregation. Magnesium Isoglycyrrhizinate (MgIG) has been accepted to be a neuroprotective effect, hepatoprotective and anti-inflammatory mol. In our vitro researches, MgIG was considered to activate hepatic stellate cells (HSCs) apoptosis by promoting endoplasmic reticulum stress (ERS) detrimental response to a certain extent. Consequently, MgIG showed its potential therapeutic capacity in fibrogenesis and counteracted the pathogenetic aspects, which were involved in integrating current treatments correcting liver fibrosis. In addn., we further verificated the behavior and pathogenic mechanisms in the CCl4-induced liver fibrosis in male mice. What surprised us was that with the treatment of MgIG caused the activation of ERS and resisted the activated HSCs in the protective effects on liver damage. We found MgIG significantly promoted the apoptosis of activated HSCs and protected the CCl4-induced liver fibrosis. Main mols. came down to the unfolded protein response signaling pathway. Furthermore, MgIG inhibited the levels of the downstream inflammatory cytokines, which were triggered by CCl4-induced liver fibrosis. Here, we reported that MgIG improved behavioral impairments induced by i.p. injection of CCl4 and decreased the expression of proinflammatory factor, which indicated the preserving effects on liver fibrosis. © 2017 BioFactors, 2017.
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    Raoof, M.; Corr, S. J.; Zhu, C.; Cisneros, B. T.; Kaluarachchi, W. D.; Phounsavath, S.; Wilson, L. J.; Curley, S. A. Gold nanoparticles and radiofrequency in experimental models for hepatocellular carcinoma. Nanomedicine 2014, 10, 1121– 1130,  DOI: 10.1016/j.nano.2014.03.004
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    Gold nanoparticles and radiofrequency in experimental models for hepatocellular carcinoma
    Raoof, Mustafa; Corr, Stuart J.; Zhu, Cihui; Cisneros, Brandon T.; Kaluarachchi, Warna D.; Phounsavath, Sophia; Wilson, Lon J.; Curley, Steven A.
    Nanomedicine (New York, NY, United States) (2014), 10 (6), 1121-1130CODEN: NANOBF; ISSN:1549-9634. (Elsevier)
    Hepatocellular carcinoma (HCC) is one of the most lethal and chemo-refractory cancers, clearly, alternative treatment strategies are needed. We utilized 10 nm gold nanoparticles as a scaffold to synthesize nanoconjugates bearing a targeting antibody (cetuximab, C225) and gemcitabine. Loading efficiency of gemcitabine on the gold nanoconjugates was 30%. Targeted gold nanoconjugates in combination with RF were selectively cytotoxic to EGFR expressing Hep3B and SNU449 cells when compared to isotype particles with/without RF (P < 0.05). In animal expts., targeted gold nanoconjugates halted the growth of s.c. Hep3B xenografts in combination with RF exposure (P < 0.05). These xenografts also demonstrated increased apoptosis, necrosis and decreased proliferation compared to controls. Normal tissues were unharmed. We have demonstrated that non-invasive RF-induced hyperthermia when combined with targeted delivery of gemcitabine is more effective and safe at dosages ∼ 275-fold lower than the current clin.-delivered systemic dose of gemcitabine.In a model of hepatocellular carcinoma, the authors demonstrate that non-invasive RF-induced hyperthermia applied with cetuximab targeted delivery of Au NP-gemcitabine conjugate is more effective and safe at dosages ∼ 275-fold lower than the current clin.-used systemic dose of gemcitabine.
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    Newell, P.; Villanueva, A.; Friedman, S. L.; Koike, K.; Llovet, J. M. Experimental models of hepatocellular carcinoma. J. Hepatol. 2008, 48, 858– 879,  DOI: 10.1016/j.jhep.2008.01.008
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    Newell, Philippa; Villanueva, Augusto; Friedman, Scott L.; Koike, Kazuhiko; Llovet, Josep M.
    Journal of Hepatology (2008), 48 (5), 858-879CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)
    A review. Hepatocellular carcinoma (HCC) is a common and deadly cancer whose pathogenesis is incompletely understood. Comparative genomic studies from human HCC samples have classified HCCs into different mol. subgroups; yet, the unifying feature of this tumor is its propensity to arise upon a background of inflammation and fibrosis. This review seeks to analyze the available exptl. models in HCC research and to correlate data from human populations with them in order to consolidate our efforts to date, as it is increasingly clear that different models will be required to mimic different subclasses of the neoplasm. These models will be instrumental in the evaluation of compds. targeting specific mol. pathways in future preclin. studies.
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    Reyes-Gordillo, K.; Shah, R.; Arellanes-Robledo, J.; Cheng, Y.; Ibrahim, J.; Tuma, P. L. Akt1 and Akt2 isoforms play distinct roles in regulating the development of inflammation and fibrosis associated with alcoholic liver disease. Cells 2019, 8, 1337,  DOI: 10.3390/cells8111337
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    Akt1 and Akt2 isoforms play distinct roles in regulating the development of inflammation and fibrosis associated with alcoholic liver disease
    Reyes-Gordillo, Karina; Shah, Ruchi; Arellanes-Robledo, Jaime; Cheng, Ying; Ibrahim, Joseph; Tuma, Pamela L.
    Cells (2019), 8 (11), 1337CODEN: CELLC6; ISSN:2073-4409. (MDPI AG)
    Akt kinase isoforms (Akt1, Akt2, and Akt3) have generally been thought to play overlapping roles in phosphoinositide 3-kinase (PI3K)-mediated-signaling. However, recent studies have suggested that they display isoform-specific roles in muscle and fat. To det. whether such isoform-specificity is obsd. with respect to alc. liver disease (ALD) progression, we examd. the role of Akt1, Akt2, and Akt3 in hepatic inflammation, and pro-fibrogenic proliferation and migration using Kupffer cells, hepatic stellate cells (HSC), and hepatocytes in an ethanol and lipopolysaccharide (LPS)-induced two-hit model in vitro and in vivo. We detd. that siRNA-directed silencing of Akt2, but not Akt1, significantly suppressed cell inflammatory markers in HSC and Kupffer cells. Although both Akt1 and Akt2 inhibited cell proliferation in HSC, only Akt2 inhibited cell migration. Both Akt1 and Akt2, but not Akt3, inhibited fibrogenesis in hepatocytes and HSC. In addn., our in vivo results show that administration of chronic ethanol, binge ethanol and LPS (EBL) in wild-type C57BL/6 mice activated all three Akt isoforms with concomitant increases in activated forms of phosphoinositide dependent kinase-1 (PDK1), mammalian target-of-rapamycin complex 2 (mTORC2), and PI3K, resulting in upregulation in expression of inflammatory, proliferative, and fibrogenic genes. Moreover, pharmacol. blocking of Akt2, but not Akt1, inhibited EBL-induced inflammation while blocking of both Akt1 and Akt2 inhibited pro-fibrogenic marker expression and progression of fibrosis. Our findings indicate that Akt isoforms play unique roles in inflammation, cell proliferation, migration, and fibrogenesis during EBL-induced liver injury. Thus, close attention must be paid when targeting all Akt isoforms as a therapeutic intervention.
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  • Abstract

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    Scheme 1

    Scheme 1. Synthesis of Gold(I)–NHC Complexes
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    Figure 1

    Figure 1. Crystal structure of the iodo–gold(I)–NHC complex 6.

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    Figure 2

    Figure 2. Complex 6 inhibited the TrxR expression. (A) Inhibition to the activity of purified TrxR by complex 6. (B) In HepG2 cells after treatment with complex 6 for 48 and 72 h. (C) mRNA levels of TrxR. (D) Immunofluorescence analysis (original magnification is 40×). (E and F) Western blot analysis. Error bars are the SD, n = 3. Statistical significance of differences in mean values are *p < 0.05, **p < 0.01, and ***p < 0.001. Scale bars are 25 μm.

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    Figure 3

    Figure 3. Complex 6 induced ROS production and mitochondrial dysfunction. (A and B) Bright field image and ROS positive cells after treatment with complex 6 by DCFH-DA and DHE assays (original magnification is 20×), respectively. (C) Mitochondrial membrane damage imaged by JC-1 staining (original magnification is 40×). Scale bars are 25 μm.

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    Figure 4

    Figure 4. Complex 6 induced HepG2 cells apoptosis. (A and B) Apoptotic cells after treatment with complex 6 for 72 h. (C–F) Western blot analysis of apoptosis factors after treatment with complex 6 for 24 h. Error bars are the SD, n = 3. Statistical significance of differences in mean values are *p < 0.05, **p < 0.01, and ***p < 0.001.

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    Figure 5

    Figure 5. Cell cycle analysis. (A and B) Effects of complex 6 on cell cycle progression. (C and D) Western blot analysis. Error bars are the SD, n = 3. Statistical significance of differences in mean values are *p < 0.05, **p < 0.01, and ***p < 0.001.

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    Figure 6

    Figure 6. The activation of ROS is required for complex 6 to inhibit TrxR expression and induce HepG2 cell apoptosis. (A) Immunofluorescence analysis of TrxR in HepG2 cells treated with complex 6 and NAC at 37 °C for 24 h (original magnification is 40 × ). (B and C) Western blot assays. (D) Immunofluorescence analysis (original magnification is 40×). (E and F) Western blot analysis. Error bars are the SD, n = 3. Statistical significance of differences in mean values are *p < 0.05 and ***p < 0.001. Scale bars are 25 μm.

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    Figure 7

    Figure 7. Complex 6 inhibited HepG2 xenograft tumor growth in nude mice. (A) The tumor volume of HepG2 xenografts in nude mice. (B) Body weight of the mice. (C) Tumor weights in nude mice. (D) Images of the representative tumors. (E and F) H&E staining of the major organs and tumor tissues (original magnification is 20×). For the statistics of each panel in this figure, data are expressed as the mean ± SD (n = 4); ###p < 0.001 compared with the model and ***p < 0.001 compared with cisplatin.

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    Figure 8

    Figure 8. Complex 6 reduced TrxR activity in tumor tissues. (A and E) The expression of TrxR and AIF, respectively in tumor tissues using immunohistochemistry assays (original magnification is 20×). (B and F) Immunofluorescence assays; DAPI was used to stain the nucleus (original magnification is 40 × ). The scale bar is 100 μm. (C) TrxR activity in tumor tissues using the TrxR activity detection kit. (C, D, G, and H) Western blot assays in tumor tissue lysates. β-Actin was used as a protein loading control. For the statistics of each panel in this figure, data are expressed as the mean ± SD, n = 4; #p < 0.05, ##p < 0.01, and ###p < 0.001 compared with the model and *p < 0.05 and ***p < 0.001 compared with cisplatin.

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    Figure 9

    Figure 9. Complex 6 reduced the accumulation of collagen and ameliorated the damage of liver tissues in vivo. (A) The liver morphological changes. (B) H&E staining in liver tissues. (C and D) Masson and Sirius red staining. (E–H) Determination of serum ALT, AST, LDH, and TrxR levels, respectively. The original magnification is20×. For the statistics of each panel in this figure, data are expressed as the mean ± SD, n = 5; ###p < 0.001 compared with the control and *p < 0.05, **p < 0.01, and ***p < 0.001 compared with the CCl4 group.

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    Figure 10

    Figure 10. Complex 6 ameliorated the inflammatory reaction to relieve liver injury. (A and C) Liver tissues were stained with immunofluorescence using antibodies against TNF-α and IL-1β. DAPI was used to stain the nucleus. The original magnification is 40 ×. (B and D) Immunohistochemistry staining. The original magnification is 20 ×.

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  • References

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      Chemical biology of anticancer gold(III) and gold(I) complexes
      Zou, Taotao; Lum, Ching Tung; Lok, Chun-Nam; Zhang, Jing-Jing; Che, Chi-Ming
      Chemical Society Reviews (2015), 44 (24), 8786-8801CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      Gold complexes have recently gained increasing attention in the design of new metal-based anticancer therapeutics. Gold(III) complexes are generally reactive/unstable under physiol. conditions via intracellular redox reactions, and the intracellular AuIII to AuI redn. reaction has recently been "traced" by the introduction of appropriate fluorescent ligands. Similar to most Au(I) complexes, Au(III) complexes can inhibit the activities of thiol-contg. enzymes, including thioredoxin reductase, via ligand exchange reactions to form Au-S(Se) bonds. Nonetheless, there are examples of physiol. stable Au(III) and Au(I) complexes, such as [Au(TPP)]Cl (H2TPP = 5,10,15,20-tetraphenylporphyrin) and [Au(dppe)2]Cl (dppe = 1,2-bis(diphenylphosphanyl)ethane), which are known to display highly potent in vitro and in vivo anticancer activities. In this review, we summarize our current understanding of anticancer gold complexes, including their mechanisms of action and the approaches adopted to improve their anticancer efficiency. Some recent examples of gold anticancer chemotherapeutics are highlighted.
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    8. 8
      Berners-Price, S. J.; Filipovska, A. Gold compounds as therapeutic agents for human diseases. Metallomics 2011, 3, 863– 873,  DOI: 10.1039/c1mt00062d
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      8
      Gold compounds as therapeutic agents for human diseases
      Berners-Price, Susan J.; Filipovska, Aleksandra
      Metallomics (2011), 3 (9), 863-873CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
      A review. The application of gold in medicine is traceable for several thousand years and Au(I) compds. have been used clin. to treat rheumatoid arthritis since the last century. Recently research into gold-based drugs for a range of human diseases has seen a renaissance. Old as well as new Au(I) and Au(III) compds. have been used and designed with an aim of targeting cellular components that are implicated in the onset or progression of cancers, rheumatoid arthritis, viral and parasitic diseases. In addn., new disease targets have been found for gold compds. that have given insight into the mechanism of action of these compds., as well as in the mol. pathophysiol. of human diseases. Here we discuss the rationale for the design and use of gold compds. that have specific and selective targets in cells to alleviate the symptoms of a range of human diseases. We summarize the most recent findings in this research and our own discoveries to show that gold compds. can be developed to become versatile and powerful drugs for diseases caused by dysfunction of selenol and thiol contg. proteins.
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    9. 9
      Bertrand, B.; Casini, A. A golden future in medicinal inorganic chemistry: the promise of anticancer gold organometallic compounds. Dalton Trans. 2014, 43, 4209– 4219,  DOI: 10.1039/C3DT52524D
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      9
      A golden future in medicinal inorganic chemistry: the promise of anticancer gold organometallic compounds
      Bertrand, Benoit; Casini, Angela
      Dalton Transactions (2014), 43 (11), 4209-4219CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
      A review. From wedding rings on fingers to stained glass windows, by way of Olympic medals, gold has been highly prized for millennia. Nowadays, organometallic gold compds. occupy an important place in the field of medicinal inorg. chem. due to their unique chem. properties with respect to gold coordination compds. In fact, several studies have proved that they can be used to develop highly efficient metal-based drugs with possible applications in the treatment of cancer. This Perspective summarizes the results obtained for different families of bioactive organometallic gold compds. including cyclometallated gold(III) complexes with C,N-donor ligands, gold(I) and gold(I/III) N-heterocyclic (NHC) carbene complexes, as well as gold(I) alkynyl complexes, with promising anticancer effects. Most importantly, we will focus on recent developments in the field and discuss the potential of this class of organometallic compds. in relation to their versatile chem. and innovative mechanisms of action.
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    10. 10
      Zhang, X.; Selvaraju, K.; Saei, A. A.; D’Arcy, P.; Zubarev, R. A.; Arner, E. S.; Linder, S. Repurposing of auranofin: thioredoxin reductase remains a primary target of the drug. Biochimie 2019, 162, 46– 54,  DOI: 10.1016/j.biochi.2019.03.015
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      10
      Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug
      Zhang, Xiaonan; Selvaraju, Karthik; Saei, Amir Ata; D'Arcy, Padraig; Zubarev, Roman A.; Arner, Elias SJ.; Linder, Stig
      Biochimie (2019), 162 (), 46-54CODEN: BICMBE; ISSN:0300-9084. (Elsevier Masson SAS)
      Auranofin is a gold (I)-contg. compd. used for the treatment of rheumatic arthritis. Auranofin has anticancer activity in animal models and is approved for clin. trials for lung and ovarian carcinomas. Both the cytosolic and mitochondrial forms of the selenoprotein thioredoxin reductase (TrxR) are well documented targets of auranofin. Auranofin was recently reported to also inhibit proteasome activity at the level of the proteasome-assocd. deubiquitinases (DUBs) UCHL5 and USP14. We here set out to re-examine the mol. mechanism underlying auranofin cytotoxicity towards cultured cancer cells. The effects of auranofin on the proteasome were examd. in cells and in vitro, effects on DUB activity were assessed using different substrates. The cellular response to auranofin was compared to that of the 20S proteasome inhibitor bortezomib and the 19S DUB inhibitor b-AP15 using proteomics. Auranofin was found to inhibit mitochondrial activity and to an induce oxidative stress response at IC50 doses. At 2-3-fold higher doses, auranofin inhibits proteasome processing in cells. At such supra-pharmacol. concns. USP14 activity was inhibited. Anal. of protein expression profiles in drug-exposed tumor cells showed that auranofin induces a response distinct from that of the 20S proteasome inhibitor bortezomib and the DUB inhibitor b-AP15, both of which induced similar responses. Our results support the notion that the primary mechanism of action of auranofin is TrxR inhibition and suggest that proteasome DUB inhibition is an off-target effect. Whether proteasome inhibition will contribute to the antineoplastic effect of auranofin in treated patients is unclear but remains a possibility.
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    11. 11
      Marzo, T.; Massai, L.; Pratesi, A.; Stefanini, M.; Cirri, D.; Magherini, F.; Becatti, M.; Landini, I.; Nobili, S.; Mini, E.; Crociani, O.; Arcangeli, A.; Pillozzi, S.; Gamberi, T.; Messori, L. Replacement of the thiosugar of auranofin with iodide enhances the anticancer potency in a mouse model of ovarian cancer. ACS Med. Chem. Lett. 2019, 10, 656– 660,  DOI: 10.1021/acsmedchemlett.9b00007
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      11
      Replacement of the Thiosugar of Auranofin with Iodide Enhances the Anticancer Potency in a Mouse Model of Ovarian Cancer
      Marzo, Tiziano; Massai, Lara; Pratesi, Alessandro; Stefanini, Matteo; Cirri, Damiano; Magherini, Francesca; Becatti, Matteo; Landini, Ida; Nobili, Stefania; Mini, Enrico; Crociani, Olivia; Arcangeli, Annarosa; Pillozzi, Serena; Gamberi, Tania; Messori, Luigi
      ACS Medicinal Chemistry Letters (2019), 10 (4), 656-660CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      In recent years, a few successful attempts were made to repurpose the clin. approved antiarthritic gold drug, Auranofin (AF), as an anticancer agent. The present study shows that the iodido(triethylphosphine)gold(I) complex, (Et3PAuI hereafter)-an AF analog where the thiosugar ligand is simply replaced by one iodide ligand-manifests a soln. chem. resembling that of AF and exerts similar cytotoxic and proapoptotic effects on A2780 human ovarian cancer cells in vitro. However, when evaluated in a preclin. orthotopic model of ovarian cancer, Et3PAuI produces a far superior anticancer action than AF inducing a nearly complete tumor remission. The highly promising in vivo performances here documented for Et3PAuI warrant its further evaluation as a drug candidate for ovarian cancer treatment.
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    12. 12
      Sze, J. H.; Raninga, P. V.; Nakamura, K.; Casey, M.; Khanna, K. K.; Berners-Price, S. J.; Di Trapani, G.; Tonissen, K. F. Anticancer activity of a Gold(I) phosphine thioredoxin reductase inhibitor in multiple myeloma. Redox Biol. 2020, 28, 101310,  DOI: 10.1016/j.redox.2019.101310
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      12
      Anticancer activity of a Gold(I) phosphine thioredoxin reductase inhibitor in multiple myeloma
      Sze, Jun Hui; Raninga, Prahlad V.; Nakamura, Kyohei; Casey, Mika; Khanna, Kum Kum; Berners-Price, Susan J.; Di Trapani, Giovanna; Tonissen, Kathryn F.
      Redox Biology (2020), 28 (), 101310CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)
      Multiple myeloma (MM), the second most common haematol. malignancy, is a clonal plasma B-cell neoplasm that forms within the bone marrow. Despite recent advancements in treatment, MM remains an incurable disease. Auranofin, a linear gold(I) phosphine compd., has previously been shown to exert a significant anti-myeloma activity by inhibiting thioredoxin reductase (TrxR) activity. A bis-chelated tetrahedral gold(I) phosphine complex [Au(d2pype)2]Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane) was previously designed to improve the gold(I) compd. selectivity towards selenol- and thiol-contg. proteins, such as TrxR. In this study, it show that [Au(d2pype)2]Cl significantly inhibited TrxR activity in both bortezomib-sensitive and resistant myeloma cells, which led to a significant redn. in cell proliferation and induction of apoptosis, both of which were dependent on ROS. In clonogenic assays, treatment with [Au(d2pype)2]Cl completely abrogated the tumorigenic capacity of MM cells, whereas auranofin was less effective. It also show that [Au(d2pype)2]Cl exerted a significant anti-myeloma activity in vivo in human RPMI8226 xenograft model in immunocompromised NOD/SCID mice. The MYC oncogene, known to drive myeloma progression, was downregulated in both in vitro and in vivo models when treated with [Au(d2pype)2]Cl. This study highlights the "proof of concept" that improved gold(I)-based compds. could potentially be used to not only treat MM but as an alternative tool to understand the role of the Trx system in the pathogenesis of this blood disease.
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    13. 13
      Lee, D.; Xu, I. M. J.; Chiu, D. K. C.; Leibold, J.; Tse, A. P. W.; Bao, M. H. R.; Yuen, V. W. H.; Chan, C. Y. K.; Lai, R. K. H.; Chin, D. W. C.; Chan, D. F. F.; Cheung, T. T.; Chok, S. H.; Wong, C. M.; Lowe, S. W.; Ng, I. O. L.; Wong, C. C. L. Induction of oxidative stress through inhibition of thioredoxin reductase 1 is an effective therapeutic approach for hepatocellular carcinoma. Hepatology 2019, 69, 1768– 1786,  DOI: 10.1002/hep.30467
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      13
      Induction of Oxidative Stress Through Inhibition of Thioredoxin Reductase 1 Is an Effective Therapeutic Approach for Hepatocellular Carcinoma
      Lee, Derek; Xu, Iris Ming-Jing; Chiu, David Kung-Chun; Leibold, Josef; Tse, Aki Pui-Wah; Bao, Macus Hao-Ran; Yuen, Vincent Wai-Hin; Chan, Cerise Yuen-Ki; Lai, Robin Kit-Ho; Chin, Don Wai-Ching; Chan, Daniel For-Fan; Cheung, Tan-To; Chok, Siu-Ho; Wong, Chun-Ming; Lowe, Scott W.; Ng, Irene Oi-Lin; Wong, Carmen Chak-Lui
      Hepatology (Hoboken, NJ, United States) (2019), 69 (4), 1768-1786CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)
      Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide which lacks effective treatment. Cancer cells experience high levels of oxidative stress due to increased generation of reactive oxygen species (ROS). Increased antioxidant-producing capacity is therefore found in cancer cells to counteract oxidative stress. The thioredoxin system is a ubiquitous mammalian antioxidant system which scavenges ROS, and we demonstrate that it is vital for HCC growth as it maintains intracellular redn.-oxidn. (redox) homeostasis. Transcriptome sequencing in human HCC samples revealed significant overexpression of thioredoxin reductase 1 (TXNRD1), the cytosolic subunit and key enzyme of the thioredoxin system, with significant correlations to poorer clinicopathol. features and patient survival. Driven by the transcriptional activation of nuclear factor (erythroid-derived 2)-like 2, the master protector against oxidative stress, TXNRD1 counteracts intracellular ROS produced in human HCC. Inhibition of TXNRD1 through genetic inhibition hindered the proliferation of HCC cells and induced apoptosis in vitro. Administration of the pharmacol. TXNRD1 inhibitor auranofin (AUR) effectively suppressed the growth of HCC tumors induced using the hydrodynamic tail vein injection and orthotopic implantation models in vivo. Furthermore, AUR sensitized HCC cells toward the conventional therapeutic sorafenib. Conclusion: Our study highlights the reliance of HCC cells on antioxidants for redox homeostasis and growth advantage; targeting TXNRD1 resulted in dramatic accumulation of ROS, which was found to be an effective approach for the suppression of HCC tumor growth.
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    14. 14
      Rackham, O.; Shearwood, A. M.; Thyer, R.; McNamara, E.; Davies, S. M.; Callus, B. A.; Miranda-Vizuete, A.; Berners-Price, S. J.; Cheng, Q.; Arner, E. S.; Filipovska, A. Substrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: implications for development of specific inhibitors. Free Radical Biol. Med. 2011, 50, 689– 699,  DOI: 10.1016/j.freeradbiomed.2010.12.015
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      14
      Substrate and inhibitor specificities differ between human cytosolic and mitochondrial thioredoxin reductases: Implications for development of specific inhibitors
      Rackham, Oliver; Shearwood, Anne-Marie J.; Thyer, Ross; McNamara, Elyshia; Davies, Stefan M. K.; Callus, Bernard A.; Miranda-Vizuete, Antonio; Berners-Price, Susan J.; Cheng, Qing; Arner, Elias S. J.; Filipovska, Aleksandra
      Free Radical Biology & Medicine (2011), 50 (6), 689-699CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
      The cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) and thioredoxins (Trx1 and Trx2) are key components of the mammalian thioredoxin system, which is important for antioxidant defense and redox regulation of cell function. TrxR1 and TrxR2 are selenoproteins generally considered to have comparable properties, but to be functionally sepd. by their different compartments. To compare their properties we expressed recombinant human TrxR1 and TrxR2 and detd. their substrate specificities and inhibition by metal compds. TrxR2 preferred its endogenous substrate Trx2 over Trx1, whereas TrxR1 efficiently reduced both Trx1 and Trx2. TrxR2 displayed strikingly lower activity with dithionitrobenzoic acid (DTNB), lipoamide, and the quinone substrate juglone compared to TrxR1, and TrxR2 could not reduce lipoic acid. However, Sec-deficient two-amino-acid-truncated TrxR2 was almost as efficient as full-length TrxR2 in the redn. of DTNB. We found that the gold(I) compd. auranofin efficiently inhibited both full-length TrxR1 and TrxR2 and truncated TrxR2. In contrast, some newly synthesized gold(I) compds. and cisplatin inhibited only full-length TrxR1 or TrxR2 and not truncated TrxR2. Surprisingly, one gold(I) compd., [Au(d2pype)2]Cl, was a better inhibitor of TrxR1, whereas another, [(iPr2Im)2Au]Cl, mainly inhibited TrxR2. These compds. also inhibited TrxR activity in the cytoplasm and mitochondria of cells, but their cytotoxicity was not always dependent on the proapoptotic proteins Bax and Bak. In conclusion, this study reveals significant differences between human TrxR1 and TrxR2 in substrate specificity and metal compd. inhibition in vitro and in cells, which may be exploited for development of specific TrxR1- or TrxR2-targeting drugs.
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    15. 15
      Li, C.; Peng, Y.; Mao, B.; Qian, K. Thioredoxin reductase: a novel, independent prognostic marker in patients with hepatocellular carcinoma. Oncotarget 2015, 6, 17792– 17804,  DOI: 10.18632/oncotarget.3785
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      15
      Thioredoxin reductase: a novel, independent prognostic marker in patients with hepatocellular carcinoma
      Li Chunyan; Li Chunyan; Peng Yan; Mao Binglang; Qian Kun
      Oncotarget (2015), 6 (19), 17792-804 ISSN:.
      Here we found that hepatocellular carcinoma (HCC) patients with recurrence outcome and nonsurvivors had significantly increased thioredoxin reductase (TrxR) serum levels on reoperation (P < 0.0001 and P < 0.0001). Multivariate regression analysis adjusted for common risk factors showed that TrxR was an independent predictor of recurrence (hazard ratios [HR] = 4.19; 95% confidence intervals [CI]: 3.21-7.08) and overall survival (HR = 5.56; 95% CI: 3.42-10.21). The area under the receiver operating characteristic curve of TrxR was 0.837 (95% CI, 0.794-0.881) for recurrence outcome and 0.901 (95% CI, 0.869-0.933) for mortality, which was superior to high-sensitivity-C-reactive protein and a-fetoprotein (P < 0.001). The preoperative serum TrxR level is an independent and significant indicator predictive of poor prognosis and early recurrence in patients with HCC, which offering reliable information for predicting survival.
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    16. 16
      Zheng, X.; Ma, W.; Sun, R.; Yin, H.; Lin, F.; Liu, Y.; Xu, W.; Zeng, H. Butaselen prevents hepatocarcinogenesis and progression through inhibiting thioredoxin reductase activity. Redox Biol. 2018, 14, 237– 249,  DOI: 10.1016/j.redox.2017.09.014
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      16
      Butaselen prevents hepatocarcinogenesis and progression through inhibiting thioredoxin reductase activity
      Zheng, Xiaoqing; Ma, Weiwei; Sun, Ruoxuan; Yin, Hanwei; Lin, Fei; Liu, Yuxi; Xu, Wei; Zeng, Huihui
      Redox Biology (2018), 14 (), 237-249CODEN: RBEIB3; ISSN:2213-2317. (Elsevier B.V.)
      Hepatocellular carcinoma (HCC) accounts for most of primary liver cancer, of which five-year survival rate remains low and chemoprevention has become a strategy to reduce disease burden of HCC. We aim to explore the in vivo chemopreventive effect of an organoselenium-contg. compd. butaselen (BS) against hepatocarcinogenesis and its underlying mechanisms. Pre- and sustained BS treatment (9, 18 and 36 mg/Kg BS) could dose-dependently inhibit chronic hepatic inflammation, fibrosis, cirrhosis and HCC on murine models with 24 wk treatment scheme. The thioredoxin reductase (TrxR), NF-κB pathway and pro-inflammatory factors were activated during hepatocarcinogenesis, while their expression were decreased by BS treatment. BS treatment could also significantly reduce tumor vol. in H22-bearing models and remarkably slow tumor growth. HCC cell lines HepG2, Bel7402 and Huh7 were time- and dose-dependently inhibited by BS treatment. G2/M arrest and apoptosis were obsd. in HepG2 cells after BS treatment, which were mediated by TrxR/Ref-1 and NF-κB pathways inhibition. BS generated reactive oxygen species (ROS), which could be reduced by antioxidant N-acetyl-L-cysteine (NAC) and NADPH oxidase inhibitor DPI. NAC could markedly increase HepG2 cells viability. TrxR activity of HepG2 cells treated with BS were significantly decreased in parallel with proliferative inhibition. The TrxR1-knockdown HepG2 cells also exhibited low TrxR1 activity, high ROS level, relatively low proliferation rate and increased resistance to BS treatment. In conclusion, BS can prevent hepatocarcinogenesis through inhibiting chronic inflammation, cirrhosis and tumor progression. The underlying mechanisms may include TrxR activity inhibition, leading to ROS elevation, G2/M arrest and apoptosis.
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    17. 17
      Zhang, L.; Cheng, Q.; Zhang, L.; Wang, Y.; Merrill, G. F.; Ilani, T.; Fass, D.; Arnér, E. S. J.; Zhang, J. Serum thioredoxin reductase is highly increased in mice with hepatocellular carcinoma and its activity is restrained by several mechanisms. Free Radical Biol. Med. 2016, 99, 426– 435,  DOI: 10.1016/j.freeradbiomed.2016.08.028
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      17
      Serum thioredoxin reductase is highly increased in mice with hepatocellular carcinoma and its activity is restrained by several mechanisms
      Zhang, Le; Cheng, Qing; Zhang, Longjie; Wang, Yijun; Merrill, Gary F.; Ilani, Tal; Fass, Deborah; Arner, Elias S. J.; Zhang, Jinsong
      Free Radical Biology & Medicine (2016), 99 (), 426-435CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
      Increased thioredoxin reductase (TrxR) levels in serum were recently identified as possible prognostic markers for human prostate cancer or hepatocellular carcinoma. We had earlier shown that serum levels of TrxR protein are very low in healthy mice, but can in close correlation to alanine aminotransferase (ALT) increase more than 200-fold upon chem. induced liver damage. We also found that enzymic TrxR activity in serum is counteracted by a yet unidentified oxidase activity in serum. In the present study we found that mice carrying H22 hepatocellular carcinoma tumors present highly increased levels of TrxR in serum, similarly to that reported in human patients. In this case ALT levels did not parallel those of TrxR. We also discovered here that the TrxR-antagonistic oxidase activity in serum is due to the presence of quiescin Q6 sulfhydryl oxidase 1 (QSOX1). We furthermore found that the chemotherapeutic agents cisplatin or auranofin, when given systemically to H22 tumor bearing mice, can further inhibit TrxR activities in serum. The TrxR serum activity was also inhibited by endogenous electrophilic inhibitors, found to increase in tumor-bearing mice and to include protoporphyrin IX (PpIX) and 4-hydroxynonenal (HNE). Thus, hepatocellular carcinoma triggers high levels of serum TrxR that are not paralleled by ALT, and TrxR enzyme activity in serum is counteracted by several different mechanisms. The physiol. role of TrxR in serum, if any, as well as its potential value as a prognostic marker for tumor progression, needs to be studied further.
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      Bertrand, B.; Williams, M. R. M.; Bochmann, M. Gold(III) complexes for antitumor applications: an overview. Chem. - Eur. J. 2018, 24, 11840– 11851,  DOI: 10.1002/chem.201800981
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      18
      Gold(III) Complexes for Antitumor Applications: An Overview
      Bertrand, Benoit; Williams, Morwen R. M.; Bochmann, Manfred
      Chemistry - A European Journal (2018), 24 (46), 11840-11851CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Gold(III) complexes have emerged as a versatile and effective class of metal-based anticancer agents. The development of various types of ligands capable of stabilizing the AuIII cation and preventing its redn. under physiol. conditions, such as chelating nitrogen-donors, dithiocarbamates and ĈN cyclometalled ligands, has opened the way for the exploration of their potential intracellular targets and action mechanisms. At the same time, the bioconjugation of AuIII complexes has emerged as a promising strategy for improving the selectivity of this class of compds. for cancer cells over healthy tissues, and recent developments have shown that combining gold complexes with mol. structures that are specifically recognized by the cell can exploit the cell's own transport mechanisms to improve selective metal uptake.
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      Gust, R.; Ott, I.; Posselt, D.; Sommer, K. Development of cobalt(3,4-diarylsalen) complexes as tumor therapeutics. J. Med. Chem. 2004, 47, 5837– 5846,  DOI: 10.1021/jm040763n
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      19
      Development of Cobalt(3,4-diarylsalen) Complexes as Tumor Therapeutics
      Gust, Ronald; Ott, Ingo; Posselt, Diana; Sommer, Klaus
      Journal of Medicinal Chemistry (2004), 47 (24), 5837-5846CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      [1,6-Bis(2-hydroxyphenyl)-3,4-diaryl-2,5-diazahexa-1,5-diene]cobalt(II) complexes (cobalt(3,4-diarylsalen)) with 2-, 3-, or 4-OCH3/OH substituents in the 3,4-standing aryl rings were synthesized and tested for antitumor activity in vitro on the MCF-7, MDA-MB 231, and LNCaP/FGC cell lines. The cytotoxicity depended on both the configuration of the diene ligand and the kind of substituents in the 3,4-standing arom. rings. D,l-7 (2-OCH3), d,l-8 (3-OCH3), and d,l-9 (4-OCH3) were equipotent to cisplatin, while the resp. hydroxy-substituted complexes (d,l-10 (2-OH), d,l-11 (3-OH), and d,l-12 (2-OH)) as well as all of the meso-configured compds. (m-7 to m-12) did not influence the cell growth. Interestingly, a high catalytic potency and a rapid and high accumulation in MCF-7 cells (15- to 25-fold compared to the cell culture medium (5 μM)) were demonstrated for m-7 (2-OCH3), m-8 (3-OCH3), and m-9 (4-OCH3). Therefore, a mode of action based on a cobalt-catalyzed oxidative damage of the DNA is not very likely.
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      Ott, I. On the medicinal chemistry of gold complexes as anticancer drugs. Coord. Chem. Rev. 2009, 253, 1670– 1681,  DOI: 10.1016/j.ccr.2009.02.019
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      20
      On the medicinal chemistry of gold complexes as anticancer drugs
      Ott, Ingo
      Coordination Chemistry Reviews (2009), 253 (11+12), 1670-1681CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
      A review. Metal complexes have shown interesting preclin. and clin. results as antitumor drugs and platinum compds. are well established in current cancer chemotherapy. However, the platinum based treatment of tumoral diseases is massively hampered by severe side effects and resistance development. Consequently, the development of novel metallodrugs with a pharmacol. profile different from that of the platinum drugs is in the focus of modern medicinal chem. and drug design. Among the non-platinum antitumor drugs, gold complexes have recently gained considerable attention due to their strong antiproliferative potency. In many cases the cell growth inhibiting effects could be related to anti-mitochondrial effects making gold species interesting drug candidates with a mode of action different from that of the platinum agents. The spectrum of gold complexes described as antiproliferative compds. comprises a broad variety of different species including many phosphine complexes as well as gold in different oxidn. states. This presentation gives an overview of the relevant medicinal chem. of known gold complexes with in vitro and in vivo tumor growth inhibiting properties.
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    21. 21
      Schmidt, C.; Karge, B.; Misgeld, R.; Prokop, A.; Bronstrup, M.; Ott, I. Biscarbene gold(i) complexes: structure-activity-relationships regarding antibacterial effects, cytotoxicity, TrxR inhibition and cellular bioavailability. MedChemComm 2017, 8, 1681– 1689,  DOI: 10.1039/C7MD00269F
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      21
      Biscarbene gold(I) complexes: structure-activity-relationships regarding antibacterial effects, cytotoxicity, TrxR inhibition and cellular bioavailability
      Schmidt, Claudia; Karge, Bianka; Misgeld, Rainer; Prokop, Aram; Broenstrup, Mark; Ott, Ingo
      MedChemComm (2017), 8 (8), 1681-1689CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
      A series of gold(I) complexes with two N-heterocyclic carbene ligands (biscarbene gold complexes) were prepd. and evaluated for their effects against cancer cells and pathogenic bacteria. Proliferation inhibition was obsd. in cancer cells and in Gram-pos. bacteria, whereas Gram-neg. bacteria were less sensitive towards the compds. The protein binding and cellular uptake were quantified and the combined results indicated a strong correlation between cellular bioavailability and antiproliferative effects. The biscarbene gold complexes inhibited bacterial and mammalian TrxRs with low to moderate potency. However, based on the obtained structure-activity-relationships and the high cellular accumulation levels, TrxR inhibition can be considered as a relevant contributor to the cellular pharmacol. of biscarbene gold(I) complexes.
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    22. 22
      Liu, W.; Bensdorf, K.; Proetto, M.; Abram, U.; Hagenbach, A.; Gust, R. NHC gold halide complexes derived from 4,5-diarylimidazoles: synthesis, structural analysis, and pharmacological investigations as potential antitumor agents. J. Med. Chem. 2011, 54, 8605– 8615,  DOI: 10.1021/jm201156x
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      22
      NHC Gold halide complexes derived from 4,5-diarylimidazoles: synthesis, structural analysis, and pharmacological investigations as potential antitumor agents
      Liu, Wukun; Bensdorf, Kerstin; Proetto, Maria; Abram, Ulrich; Hagenbach, Adelheid; Gust, Ronald
      Journal of Medicinal Chemistry (2011), 54 (24), 8605-8615CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A series of novel neutral N-heterocyclic carbene (NHC) gold halide complexes derived from 4,5-diarylimidazoles were synthesized, characterized, and analyzed for biol. effects. High growth inhibitory effects in MCF-7 and MDA-MB 231 breast cancer as well as HT-29 colon cancer cell lines depended on the presence of the C4,C5-standing arom. rings. Methoxy groups at these rings did not change the growth inhibitory properties, while F-substituents in the ortho-position increased the activity in MCF-7 and MDA-MB 231 cells. The substituents at the nitrogen atoms and the oxidn. state of the metal play a subordinate role. The most active bromo[1,3-diethyl-4,5-bis(2-fluorophenyl)-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) (5d) was distinctly more active than cisplatin. All complexes caused thioredoxin reductase (TrxR) inhibition (EC50 = 374-1505 nM) distinctly lower than Auranofin (EC50 = 18.6 nM) excluding this enzyme as main target. Because of the low nuclear content, a participation of DNA interaction on the mode of action is very unlikely. The missing ER binding and the missing correlation of growth inhibition and inactivation of COX enzymes exclude these targets, too.
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      Liu, W.; Bensdorf, K.; Hagenbach, A.; Abram, U.; Niu, B.; Mariappan, A.; Gust, R. Synthesis and biological studies of silver N-heterocyclic carbene complexes derived from 4,5-diarylimidazole. Eur. J. Med. Chem. 2011, 46, 5927– 5934,  DOI: 10.1016/j.ejmech.2011.10.002
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      Synthesis and biological studies of silver N-heterocyclic carbene complexes derived from 4,5-diarylimidazole
      Liu, Wukun; Bensdorf, Kerstin; Hagenbach, Adelheid; Abram, Ulrich; Niu, Ben; Mariappan, Aruljothi; Gust, Ronald
      European Journal of Medicinal Chemistry (2011), 46 (12), 5927-5934CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A novel class of Ag N-heterocyclic carbene complexes, 4,5-(RC6H4)2-1-Et-3-R'C3N2AgX (5: X = Br, R' = Et, R = 2-F (a), 3-F (b), 4-F (c), 4-MeO (d), 4-OH (e); X = Cl, R' = PhCH2, R = 4-F (f)) was synthesized in 51% to 81% yield by reacting Ag(I) oxide with the appropriate 4,5-diarylimidazolium halide. The complexes were characterized using NMR and IR spectroscopy. The structure was confirmed on the example of bromo[1,3-diethyl-4,5-bis(4-fluorophenyl)imidazol-2-ylidene]silver(I) (5c) by crystal structure anal. The complexes are arranged in the crystal in dimeric units. Each metal binds one NHC and two bridging bromides. Pharmacol. studies revealed that all Ag complexes possessed growth inhibitory effects against breast cancer (MCF-7 and MDA-MB-231) as well as colon carcinoma (HT-29) cells. The most active compd. 5c was slightly less active against MCF-7 cells, more active against MDA-MB-231 cells and comparable active as cisplatin against HT-29 cells. Further pharmacol. studies were performed with selected compds. on estrogen receptor (ER) binding, DNA intercalation, cyclooxygenase (COX) inhibition and antibacterial activity. The complexes were only marginally active at the DNA, ER and the COX enzymes, so these targets can be excluded to be involved in the mode of action. However, the growth of bacteria was significantly inhibited by 5c and 5f and opens a new application of this complex type.
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      Meyer, A.; Oehninger, L.; Geldmacher, Y.; Alborzinia, H.; Wolfl, S.; Sheldrick, W. S.; Ott, I. Gold(I) N-heterocyclic carbene complexes with naphthalimide ligands as combined thioredoxin reductase inhibitors and DNA intercalators. ChemMedChem 2014, 9, 1794– 1800,  DOI: 10.1002/cmdc.201402049
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      Gold(I) N-Heterocyclic Carbene Complexes with Naphthalimide Ligands as Combined Thioredoxin Reductase Inhibitors and DNA Intercalators
      Meyer, Andreas; Oehninger, Luciano; Geldmacher, Yvonne; Alborzinia, Hamed; Woelfl, Stefan; Sheldrick, William S.; Ott, Ingo
      ChemMedChem (2014), 9 (8), 1794-1800CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Organometallic conjugates consisting of a gold(I) N-heterocyclic carbene (NHC) moiety and a naphthalimide were prepd. and investigated as cytotoxic agents that interact with both DNA and the disulfide reductase enzyme thioredoxin reductase (TrxR). The complexes were potent DNA intercalators related to their naphthalimide partial structure, inhibited TrxR as a consequence of the incorporation of the gold(I) moiety, and triggered efficient cytotoxic effects in MCF-7 breast and HT-29 colon adenocarcinoma cells. Strong effects on tumor cell metab. were noted for the most cytotoxic complex, chlorido[1-(3'-(4''-ethylthio-1'',8''-naphthalimid-N''-yl))-propyl-3-methyl-imidazol-2-ylidene]gold(I) (4 d). In conclusion, the conjugation of naphthalimides with gold(I) NHC moieties provided a useful strategy for the design of bioorganometallic anticancer agents with multiple modes of action.
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      Zou, T.; Lum, C. T.; Chui, S. S.; Che, C. M. Gold(III) complexes containing N-heterocyclic carbene ligands: thiol “switch-on” fluorescent probes and anti-cancer agents. Angew. Chem., Int. Ed. 2013, 52, 2930– 2933,  DOI: 10.1002/anie.201209787
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      Gold(III) Complexes Containing N-Heterocyclic Carbene Ligands: Thiol "Switch-on" Fluorescent Probes and Anti-Cancer Agents
      Zou, Taotao; Lum, Ching Tung; Chui, Stephen Sin-Yin; Che, Chi-Ming
      Angewandte Chemie, International Edition (2013), 52 (10), 2930-2933CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A class of Au(III) complexes bearing N-heterocyclic carbene and 2,6-bis(imidazol-2-yl)pyridine or 2,6-bis(benzimidazol-2-yl)pyridine ligands have been developed. These Au(III)-NHC complexes are sensitive towards thiols, which leads to release of fluorescent ligand, and thus can serve as a switch-on probe for thiols in biol. systems. The Au(III) complexes can also suppress tumor growth in mice bearing HeLa xenografts. These Au(III) complexes could be a promising scaffold for the future development of novel switch-on probes and anti-cancer agents.
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      Ott, I. Metal N-heterocyclic carbene complexes in medicinal chemistry. Adv. Inorg. Chem. 2020, 75, 121– 148,  DOI: 10.1016/bs.adioch.2019.10.008
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      Liu, W.; Gust, R. Metal N-heterocyclic carbene complexes as potential antitumor metallodrugs. Chem. Soc. Rev. 2013, 42, 755– 773,  DOI: 10.1039/C2CS35314H
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      Metal N-heterocyclic carbene complexes as potential antitumor metallodrugs
      Liu, Wukun; Gust, Ronald
      Chemical Society Reviews (2013), 42 (2), 755-773CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. The discovery of cisplatin's antitumor activity in 1969 prompted the search for novel metal-contg. complexes as potential anticancer drugs. Among these novel complexes, metal N-heterocyclic carbene (NHC) complexes have recently gained considerable attention because they perfectly fit prerequisites for efficient drug design and fast optimization. Moreover, most of them have shown higher cytotoxicity than cisplatin. This review describes the advances that have been achieved in using transition metal (Ag, Au, Pt, Pd, Cu, Ni, and Ru) complexes contg. NHC ligands as antitumor agents. Their modes of action at the cellular lever are further discussed. All these initial achievements clearly demonstrate the great potential of metal-NHC complexes as antitumor agents.
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      Hickey, J. L.; Ruhayel, R. A.; Barnard, P. J.; Baker, M. V.; Berners-Price, S. J.; Filipovska, A. Mitochondria-targeted chemotherapeutics: the rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols. J. Am. Chem. Soc. 2008, 130, 12570– 12571,  DOI: 10.1021/ja804027j
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      28
      Mitochondria-Targeted Chemotherapeutics: The Rational Design of Gold(I) N-Heterocyclic Carbene Complexes That Are Selectively Toxic to Cancer Cells and Target Protein Selenols in Preference to Thiols
      Hickey, James L.; Ruhayel, Rasha A.; Barnard, Peter J.; Baker, Murray V.; Berners-Price, Susan J.; Filipovska, Aleksandra
      Journal of the American Chemical Society (2008), 130 (38), 12570-12571CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A family of lipophilic, cationic Au(I) complexes of N-heterocyclic carbenes (NHCs) have been designed as new mitochondria-targeted antitumor agents that combine both selective mitochondrial accumulation and selective thioredoxin reductase inhibition properties within a single mol. Two-step ligand exchange reactions with cysteine (Cys) and selenocysteine (Sec) occur with release of the NHC ligands. At physiol. pH the rate consts. for the reactions with Sec are 20- to 80-fold higher than those with Cys. The complexes are selectively toxic to two highly tumorigenic breast cancer cell lines and not to normal breast cells, and the degree of selectivity and potency are optimized by modification of the substituent on the simple imidazolium salt precursor. The lead compd. is shown to accumulate in mitochondria of cancer cells, to cause cell death through a mitochondrial apoptotic pathway and to inhibit the activity of thioredoxin reductase (TrxR) but not the closely related and Se-free enzyme glutathione reductase.
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      Liu, W.; Gust, R. Update on metal N-heterocyclic carbene complexes as potential anti-tumor metallodrugs. Coord. Chem. Rev. 2016, 329, 191– 213,  DOI: 10.1016/j.ccr.2016.09.004
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      Update on metal N-heterocyclic carbene complexes as potential anti-tumor metallodrugs
      Liu, Wukun; Gust, Ronald
      Coordination Chemistry Reviews (2016), 329 (), 191-213CODEN: CCHRAM; ISSN:0010-8545. (Elsevier B.V.)
      The clin. success of platinum-based chemotherapeutic agents was of enormous impact on the discovery of novel metal N-heterocyclic carbene (NHC) complexes as potential anti-cancer drugs. During the last years, the research on cytotoxic transition metal (e.g. Ag, Au, Pt, Pd, Cu, Hg, Ru, Os, Rh and Ir) NHC complexes was successful and the results are remarkable. In this review, we provide an update on the recent advances in this direction, which reflects new discoveries since the publication of our previous review. The anti-tumor properties along with the mechanisms of action for these complexes as well as possible structure-activity relationships are discussed.
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    30. 30
      Schmidt, C.; Albrecht, L.; Balasupramaniam, S.; Misgeld, R.; Karge, B.; Bronstrup, M.; Prokop, A.; Baumann, K.; Reichl, S.; Ott, I. A gold(I) biscarbene complex with improved activity as a TrxR inhibitor and cytotoxic drug: comparative studies with different gold metallodrugs. Metallomics 2019, 11, 533– 545,  DOI: 10.1039/C8MT00306H
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      A gold(I) biscarbene complex with improved activity as a TrxR inhibitor and cytotoxic drug: comparative studies with different gold metallodrugs
      Schmidt, Claudia; Albrecht, Lucia; Balasupramaniam, Shantheya; Misgeld, Rainer; Karge, Bianka; Broenstrup, Mark; Prokop, Aram; Baumann, Knut; Reichl, Stephan; Ott, Ingo
      Metallomics (2019), 11 (3), 533-545CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
      Gold complexes with N-heterocyclic carbene (NHC) ligands have been attracting major attention in medicinal inorg. chem. based on their favorable antiproliferative effects and the structural versatility of the coordinated NHC ligands. Here we present a novel complex of the type (NHC)2Au+, which represents a substantially improved and selective TrxR inhibitor compared to close structural analogs. The complex is highly stable in various solns. over 96 h, however, comparative cellular uptake studies indicate metabolic transformations inside cells over time. A portfolio of other gold complexes (e.g. Auranofin) has been used as refs. in key biol. assays, showing that the novel (NHC)2Au+ complex exhibits substantially lower protein binding in combination with a strongly enhanced cytotoxic activity.
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      Baker, M. V.; Barnard, P. J.; Brayshaw, S. K.; Hickey, J. L.; Skelton, B. W.; White, A. H. Synthetic, structural and spectroscopic studies of (pseudo)halo(1,3-di-tert-butylimidazol-2-ylidine)gold complexes. Dalton Trans. 2005, 1, 37– 43,  DOI: 10.1039/b412540a
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      Messori, L.; Marchetti, L.; Massai, L.; Scaletti, F.; Guerri, A.; Landini, I.; Nobili, S.; Perrone, G.; Mini, E.; Leoni, P.; Pasquali, M.; Gabbiani, C. Chemistry and biology of two novel gold(I) carbene complexes as prospective anticancer agents. Inorg. Chem. 2014, 53, 2396– 2403,  DOI: 10.1021/ic401731a
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      Chemistry and Biology of Two Novel Gold(I) Carbene Complexes as Prospective Anticancer Agents
      Messori, Luigi; Marchetti, Lorella; Massai, Lara; Scaletti, Federica; Guerri, Annalisa; Landini, Ida; Nobili, Stefania; Perrone, Gabriele; Mini, Enrico; Leoni, Piero; Pasquali, Marco; Gabbiani, Chiara
      Inorganic Chemistry (2014), 53 (5), 2396-2403CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      Two novel gold carbene compds., namely, chloro (1-butyl-3-methyl-imidazole-2-ylidene) gold(I) (1) and bis(1-butyl-3-methyl-imidazole-2-ylidene) gold(I) (2), were prepd. and characterized as prospective anticancer drug candidates. These compds. consist of a gold(I) center linearly coordinated either to one N-heterocyclic carbene (NHC) and one chloride ligand (1) or to two identical NHC ligands (2). Crystal structures were solved for both compds., the resulting structural data being in good agreement with expectations. We wondered whether the presence of two tight carbene ligands in 2 might lead to biol. properties distinct from those of the monocarbene complex 1. Notably, in spite of their appreciable structural differences, these two compds. manifested similarly potent cytotoxic actions in vitro when challenged against A2780 human ovarian carcinoma cells. In addn., both were able to overcome resistance to cisplatin in the A2780R line. Soln. studies revealed that these gold carbene complexes are highly stable in aq. buffers at physiol. pH. Their reactivity with proteins was explored: no adduct formation was detected even upon a long incubation with the model proteins cytochrome c and lysozyme; in contrast, both compds. were able to metalate, to a large extent, the copper chaperone Atox-1, bearing a characteristic CXXC motif. The precise nature of the resulting gold-Atox-1 adducts was elucidated through ESI-MS anal. On the basis of these findings, it is proposed that the investigated gold(I) carbene compds. are promising antiproliferative agents warranting a wider pharmacol. evaluation. Most likely these gold compds. produce their potent biol. effects through selective metalation and impairment of a few crucial cellular proteins.
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    33. 33
      Marzo, T.; Cirri, D.; Gabbiani, C.; Gamberi, T.; Magherini, F.; Pratesi, A.; Guerri, A.; Biver, T.; Binacchi, F.; Stefanini, M.; Arcangeli, A.; Messori, L. Auranofin, Et3PAuCl, and Et3PAuI are highly cytotoxic on colorectal cancer cells: a chemical and biological study. ACS Med. Chem. Lett. 2017, 8, 997– 1001,  DOI: 10.1021/acsmedchemlett.7b00162
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      Auranofin, Et3PAuCl, and Et3PAuI Are Highly Cytotoxic on Colorectal Cancer Cells: A Chemical and Biological Study
      Marzo, Tiziano; Cirri, Damiano; Gabbiani, Chiara; Gamberi, Tania; Magherini, Francesca; Pratesi, Alessandro; Guerri, Annalisa; Biver, Tarita; Binacchi, Francesca; Stefanini, Matteo; Arcangeli, Annarosa; Messori, Luigi
      ACS Medicinal Chemistry Letters (2017), 8 (10), 997-1001CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      The soln. behavior of auranofin, Et3PAuCl and Et3PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward representative colorectal cancer cell lines were found to be strong and similar in the three cases and a good correlation could be established between the cytotoxicity and the ability to inhibit thioredoxin reductase; remarkably, in vivo acute toxicity expts. for Et3PAuI confirmed that, similarly to auranofin, this drug is well tolerated in a murine model. Overall, a very similar profile emerges for Et3PAuI and Et3PAuCl, which retain the potent cytotoxic effects of auranofin while showing some peculiar features. These results demonstrate that the presence of the thiosugar moiety is not mandatory for the pharmacol. action, suggesting that the tuning of some relevant chem. properties such as lipophilicity could be exploited to improve bioavailability, with no loss of the pharmacol. effects.
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      Karaca, O.; Scalcon, V.; Meier-Menches, S. M.; Bonsignore, R.; Brouwer, J.; Tonolo, F.; Folda, A.; Rigobello, M. P.; Kuhn, F. E.; Casini, A. Characterization of hydrophilic gold(I) N-heterocyclic carbene (NHC) complexes as potent TrxR inhibitors using biochemical and mass spectrometric approaches. Inorg. Chem. 2017, 56, 14237– 14250,  DOI: 10.1021/acs.inorgchem.7b02345
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      34
      Characterization of Hydrophilic Gold(I) N-Heterocyclic Carbene (NHC) Complexes as Potent TrxR Inhibitors Using Biochemical and Mass Spectrometric Approaches
      Karaca, Oezden; Scalcon, Valeria; Meier-Menches, Samuel M.; Bonsignore, Riccardo; Brouwer, Jurriaan M. J. L.; Tonolo, Federica; Folda, Alessandra; Rigobello, Maria Pia; Kuehn, Fritz E.; Casini, Angela
      Inorganic Chemistry (2017), 56 (22), 14237-14250CODEN: INOCAJ; ISSN:0020-1669. (American Chemical Society)
      The authors report on the synthesis of a series of mono- and dinuclear gold(I) complexes exhibiting sulfonated bis(NHC) ligands and novel hydroxylated mono(NHC) Au(I) compds., which were also examd. for their biol. activities. Initial cell viability assays show strong antiproliferative activities of the hydroxylated mono(NHC) gold compds. (8 > 9 > 10) against 2008 human ovarian cancer cells even after 1 h incubation. To gain insight into the mechanism of biol. action of the gold compds., their effect on the pivotal cellular target seleno-enzyme thioredoxin reductase (TrxR), involved in the maintenance of intracellular redox balance, was investigated in depth. The compds.' inhibitory effects on TrxR and glutathione reductase (GR) were studied comparatively, using either the pure proteins or cancer cell exts. The results show a strong and selective inhibitory effect of TrxR, specifically for the hydroxyl-functionalized NHC gold(I) complexes (8-10). Valuable information on the gold compds.' mol. reactivity with TrxR was gained using the BIAM (biotin-conjugated iodoacetamide) assay and performing competition expts. by mass spectrometry (MS). In good agreement, both techniques suggest the binding affinity of the mono(NHC) Au(I) complexes toward selenols and thiols. Notably, for the first time, bis-carbene formation from mono-carbenes in buffered soln. could be obsd. by MS, which may provide new insights into the speciation mechanisms of bioactive Au(I) NHC complexes. Furthermore, the compds.' interactions with another relevant in cellulo target, namely telomeric G-quadruplex DNA-a higher-order DNA structure playing key roles in telomere function-was investigated by FRET melting assays. The lack of interactions with this type of nucleic acid secondary structure support the idea of selective targeting of the hydrophilic Au(I) NHC compds. toward proteins such as TrxR.
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      Mirzayans, R.; Andrais, B.; Murray, D. Do Multiwell Plate High Throughput Assays Measure Loss of Cell Viability Following Exposure to Genotoxic Agents?. Int. J. Mol. Sci. 2017, 18, 1679,  DOI: 10.3390/ijms18081679
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      Do multiwell plate high throughput assays measure loss of cell viability following exposure to genotoxic agents?
      Mirzayans, Razmik; Andrais, Bonnie; Murray, David
      International Journal of Molecular Sciences (2017), 18 (8), 1679/1-1679/10CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      Cell-based assays in multiwell plates are widely used for radiosensitivity and chemosensitivity assessment with different mammalian cell types. Despite their relative ease of performance, such assays lack specificity as they do not distinguish between the cytostatic (reversible/sustained growth arrest) and cytotoxic (loss of viability) effects of genotoxic agents. We recently reported studies with solid tumor-derived cell lines demonstrating that radiosensitivity as measured by multiwell plate colorimetric (e.g., XTT) and fluorimetric (e.g., CellTiter-Blue) assays reflects growth arrest but not loss of viability. Herein we report similar observations with cancer cell lines expressing wild-type p53 (A549 lung carcinoma) or mutant p53 (MDA-MB-231 breast carcinoma) after treatment with the chemotherapeutic drug cisplatin. Importantly, we show that treatment of cancer cells with concns. of cisplatin that result in 50% effect (i.e., IC50) in multiwell plate assays trigger the emergence of growth arrested cells that exhibit highly enlarged morphol., remain viable and adherent to the culture dish, and metabolize the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) to its formazan deriv. The emergence of markedly enlarged viable cells complicates the interpretation of chemosensitivity data obtained with multiwell plate high throughput assays. Relying solely on IC50 values could be misleading.
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      Monteiro-Riviere, N. A.; Inman, A. O.; Zhang, L. W. Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line. Toxicol. Appl. Pharmacol. 2009, 234, 222– 235,  DOI: 10.1016/j.taap.2008.09.030
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      Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line
      Monteiro-Riviere, N. A.; Inman, A. O.; Zhang, L. W.
      Toxicology and Applied Pharmacology (2009), 234 (2), 222-235CODEN: TXAPA9; ISSN:0041-008X. (Elsevier B.V.)
      Single-walled carbon nanotubes (SWCNT), fullerenes (C60), carbon black (CB), nC60, and quantum dots (QD) have been studied in vitro to det. their toxicity in a no. of cell types. Here, the authors report that classical dye-based assays such as MTT and neutral red (NR) that det. cell viability produce invalid results with some NM (nanomaterials) due to NM/dye interactions and/or NM adsorption of the dye/dye products. In this study, human epidermal keratinocytes (HEK) were exposed in vitro to CB, SWCNT, C60, nC60, and QD to assess viability with calcein AM (CAM), Live/Dead (LD), NR, MTT, Celltiter 96 Aq. One (96 AQ), alamar Blue (aB), Celltiter-Blue (CTB), CytoTox One (CTO), and flow cytometry. In addn., trypan blue (TB) was quantitated by light microscopy. Assay linearity (R2 value) was detd. with HEK plated at concns. from 0 to 25,000 cells per well in 96-well plates. HEK were treated with serial dilns. of each NM for 24 h and assessed with each of the viability assays. TB, CAM and LD assays, which depend on direct staining of living and/or dead cells, were difficult to interpret due to phys. interference of the NM with cells. Results of the dye-based assays varied a great deal, depending on the interactions of the dye/dye product with the carbon nanomaterials (CNM). Results show the optimal high throughput assay for use with carbon and noncarbon NM was 96 AQ. This study shows that, unlike small mols., CNM interact with assay markers to cause variable results with classical toxicol. assays and may not be suitable for assessing nanoparticle cytotoxicity. Therefore, more than one assay may be required when detg. nanoparticle toxicity for risk assessment.
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    37. 37
      Ott, I.; Qian, X.; Xu, Y.; Vlecken, D. H.; Marques, I. J.; Kubutat, D.; Will, J.; Sheldrick, W. S.; Jesse, P.; Prokop, A.; Bagowski, C. P. A gold(I) phosphine complex containing a naphthalimide ligand functions as a TrxR inhibiting antiproliferative agent and angiogenesis inhibitor. J. Med. Chem. 2009, 52, 763– 770,  DOI: 10.1021/jm8012135
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      A Gold(I) Phosphine Complex Containing Naphthalimide Ligand Functions as a TrxR Inhibiting Antiproliferative Agent and Angiogenesis Inhibitor
      Ott, Ingo; Qian, Xuhong; Xu, Yufang; Vlecken, Danielle H. W.; Marques, Ines J.; Kubutat, Dominic; Will, Joanna; Sheldrick, William S.; Jesse, Patrick; Prokop, Aram; Bagowski, Christoph P.
      Journal of Medicinal Chemistry (2009), 52 (3), 763-770CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The novel luminescent gold(I) complex [N-(N',N'-dimethylaminoethyl)-1,8-naphthalimide-4-sulfide](triethylphosphine)gold(I) was prepd. and investigated for its primary biol. properties. Cell culture expts. revealed strong antiproliferative effects and induction of apoptosis via mitochondrial pathways. Biodistribution studies by fluorescence microscopy and at. absorption spectroscopy showed the uptake into cell organelles, an accumulation in the nuclei of tumor cells, and a homogeneous distribution in zebrafish embryos. In vivo monitoring of vascularization in developing zebrafish embryos revealed a significant anti-angiogenic potency of the complex. Mechanistic expts. indicated that the inhibition of thioredoxin reductase (based on the covalent binding of a gold triethylphosphine fragment) might be involved in the pharmacodynamic behavior of this novel gold species.
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      Bian, M.; Fan, R.; Zhao, S.; Liu, W. Targeting the thioredoxin system as a strategy for cancer therapy. J. Med. Chem. 2019, 62, 7309– 7321,  DOI: 10.1021/acs.jmedchem.8b01595
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      Targeting the thioredoxin system as a strategy for cancer therapy
      Bian, Mianli; Fan, Rong; Zhao, Sai; Liu, Wukun
      Journal of Medicinal Chemistry (2019), 62 (16), 7309-7321CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. Thioredoxin reductase (TrxR) participates in the regulation of redox reactions in organisms. It works mainly via its substrate mol., thioredoxin, to maintain the redox balance and regulate signal transduction, which controls cell proliferation, differentiation, death, and other important physiol. processes. In recent years, increasing evidence has shown that the overactivation of TrxR is related to the development of tumors. The exploration of TrxR-targeted antitumor drugs has attracted wide attention and is expected to provide new therapies for cancer treatment. In this perspective, we highlight the specific relationship between TrxR and apoptotic signaling pathways. The cytoplasm and mitochondria both contain TrxR, resulting in the activation of apoptosis. TrxR activity influences reactive oxygen species (ROS) and further regulates the inflammatory signaling pathway. In addn., we discuss representative TrxR inhibitors with anticancer activity and analyze the challenges in developing TrxR inhibitors as anticancer drugs.
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      Zhang, J.; Zhang, B.; Li, X.; Han, X.; Liu, R.; Fang, J. Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: an update. Med. Res. Rev. 2019, 39, 5– 39,  DOI: 10.1002/med.21507
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      Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update
      Zhang, Junmin; Zhang, Baoxin; Li, Xinming; Han, Xiao; Liu, Ruijuan; Fang, Jianguo
      Medicinal Research Reviews (2019), 39 (1), 5-39CODEN: MRREDD; ISSN:0198-6325. (John Wiley & Sons, Inc.)
      A review. Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small mol. modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small mol. inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of mols. were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive ref. in the medicinal chem., and have a broad audience across multiple disciplines.
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      Zhang, B.; Liu, Y.; Li, X.; Xu, J.; Fang, J. Small molecules to target the selenoprotein thioredoxin reductase. Chem. - Asian J. 2018, 13, 3593– 3600,  DOI: 10.1002/asia.201801136
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      Small Molecules to Target the Selenoprotein Thioredoxin Reductase
      Zhang, Baoxin; Liu, Yuxin; Li, Xinming; Xu, Jianqiang; Fang, Jianguo
      Chemistry - An Asian Journal (2018), 13 (23), 3593-3600CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. The selenoprotein thioredoxin reductase (TrxR) enzymes are the only identified proteins that maintain thioredoxin (Trx) proteins in a reduced state under physiol. conditions, and consequently play a pivotal role in the regulation of various cellular redox signaling pathways involved in cell differentiation, growth, and death. The elevated expression of TrxR enzymes has been obsd. in different types of cancer cells, and this overexpression is of pathol. significance in maintaining tumor phenotypes, such as uncontrolled proliferation and resistance to apoptosis. Herein, the authors discuss recent advances in the study of TrxR, including classic assays of TrxR, the emerging chem. tools of TrxR, and small mols. that target TrxR as potential anticancer agents.
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      Huang, K. B.; Wang, F. Y.; Tang, X. M.; Feng, H. W.; Chen, Z. F.; Liu, Y. C.; Liu, Y. N.; Liang, H. Organometallic gold(III) complexes similar to tetrahydroisoquinoline induce ER-stress-mediated apoptosis and pro-death autophagy in A549 cancer cells. J. Med. Chem. 2018, 61, 3478– 3490,  DOI: 10.1021/acs.jmedchem.7b01694
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      Organometallic Gold(III) complexes similar to tetrahydroisoquinoline induce ER-stress-mediated apoptosis and pro-death autophagy in A549 cancer cells
      Huang, Ke-Bin; Wang, Feng-Yang; Tang, Xiao-Ming; Feng, Hai-Wen; Chen, Zhen-Feng; Liu, Yan-Cheng; Liu, You-Nian; Liang, Hong
      Journal of Medicinal Chemistry (2018), 61 (8), 3478-3490CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Gold(III) cyclometalated benzeneethanamine chelate complexes exhibit high cytotoxic activity towards lung cancer cells, causing ER-controlled apoptosis and autophagy, exhibiting less toxicity compared to cisplatin. Agents inducing both apoptosis and autophagic death can be effective chemotherapeutic drugs. In our present work, we synthesized two organometallic gold(III) complexes harboring C-N ligands that structurally resemble tetrahydroisoquinoline (THIQ): Cyc-Au-1 (AuL1Cl2, HL1 = 3,4-dimethoxyphenethylamine) and Cyc-Au-2 (AuL2Cl2, HL2 = 1,3-benzodioxole-5-ethanamine). In screening their in vitro activity, we found both gold complexes exhibited lower toxicity, lower resistance factors, and better anticancer activity than those of cisplatin. The organometallic gold(III) complexes accumulate in mitochondria and induce elevated ROS and an ER stress response through mitochondrial dysfunction. These effects ultimately result in simultaneous apoptosis and autophagy. Importantly, compared to cisplatin, Cyc-Au-2 exhibits lower toxicity and better anticancer activity in a murine tumor model. To the best of our knowledge, Cyc-Au-2 is the first organometallic Au(III) compd. that induces apoptosis and autophagic death. On the basis of our results, we believe Cyc-Au-2 to be a promising anticancer agent or lead compd. for further anticancer drug development.
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      Bian, M.; Sun, Y.; Liu, Y.; Xu, Z.; Fan, R.; Liu, Z.; Liu, W. A gold(I) complex containing an oleanolic acid derivative as a potential anti-ovarian cancer agent via inhibiting TrxR and activating ROS-mediated ERS. Chem. - Eur. J. 2020, 26, 7092– 7108,  DOI: 10.1002/chem.202000045
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      A Gold(I) Complex Containing an Oleanolic Acid Derivative as a Potential Anti-Ovarian-Cancer Agent by Inhibiting TrxR and Activating ROS-Mediated ERS
      Bian, Mianli; Sun, Ying; Liu, Yuanhao; Xu, Zhongren; Fan, Rong; Liu, Ziwen; Liu, Wukun
      Chemistry - A European Journal (2020), 26 (31), 7092-7108CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Many cancer cells critically rely on antioxidant systems for cell survival and are vulnerable to further oxidative impairment triggered by agents generating reactive oxygen species (ROS). Therefore, the classical design and development of inhibitors that target antioxidant defense enzymes such as thioredoxin reductase (TrxR) can be a promising anticancer strategy. Herein, it is shown that a gold(I) complex contg. an oleanolic acid deriv. (4 b) induces apoptosis of ovarian cancer A2780 cells by activating endoplasmic reticulum stress (ERS). It can inhibit TrxR enzyme activity to elevate ROS, mediate ERS and mitochondrial dysfunction, and finally leads to cell cycle arrest and apoptosis of A2780 cells. Notably, this complex inhibits A2780 xenograft tumor growth accompanied by increased ERS level and decreased TrxR activity in tumor tissues.
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      Wang, K.; Zhu, C.; He, Y.; Zhang, Z.; Zhou, W.; Muhammad, N.; Guo, Y.; Wang, X.; Guo, Z. Restraining cancer cells by dual metabolic inhibition with a mitochondrion-targeted platinum(II) complex. Angew. Chem., Int. Ed. 2019, 58, 4638– 4643,  DOI: 10.1002/anie.201900387
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      Restraining Cancer Cells by Dual Metabolic Inhibition with a Mitochondrion-Targeted Platinum(II) Complex
      Wang, Kun; Zhu, Chengcheng; He, Yafeng; Zhang, Zhenqin; Zhou, Wen; Muhammad, Nafees; Guo, Yan; Wang, Xiaoyong; Guo, Zijian
      Angewandte Chemie, International Edition (2019), 58 (14), 4638-4643CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Cancer cells usually adapt metabolic phenotypes to chemotherapeutics. A defensive strategy against this flexibility is to modulate signaling pathways relevant to cancer bioenergetics. A triphenylphosphonium-modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabs. of cancer cells. TTP exhibited enhanced cytotoxicity against cisplatin-insensitive human ovarian cancer cells in a caspase-3-independent manner and showed preferential inhibition to mitochondrial TrxR. The morphol. and function of mitochondria were severely damaged, and the levels of mitochondrial and cellular reactive oxygen species were decreased. As a result, TTP exerted strong inhibition to both mitochondrial and glycolytic bioenergetics, thus inducing cancer cells to enter a hypometabolic state.
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      Kalyanaraman, B.; Darley-Usmar, V.; Davies, K. J.; Dennery, P. A.; Forman, H. J.; Grisham, M. B.; Mann, G. E.; Moore, K.; Roberts, L. J., 2nd; Ischiropoulos, H. Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radical Biol. Med. 2012, 52, 1– 6,  DOI: 10.1016/j.freeradbiomed.2011.09.030
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      Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations
      Kalyanaraman, Balaraman; Darley-Usmar, Victor; Davies, Kelvin J. A.; Dennery, Phyllis A.; Forman, Henry Jay; Grisham, Matthew B.; Mann, Giovanni E.; Moore, Kevin; Roberts, L. Jackson, II; Ischiropoulos, Harry
      Free Radical Biology & Medicine (2012), 52 (1), 1-6CODEN: FRBMEH; ISSN:0891-5849. (Elsevier B.V.)
      The purpose of this position paper is to present a crit. anal. of the challenges and limitations of the most widely used fluorescent probes for detecting and measuring reactive oxygen and nitrogen species. Where feasible, the authors have made recommendations for the use of alternate probes and appropriate anal. techniques that measure the specific products formed from the reactions between fluorescent probes and reactive oxygen and nitrogen species. The authors have proposed guidelines that will help present and future researchers with regard to the optimal use of selected fluorescent probes and interpretation of results.
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      Wu, K. J.; Zhong, H. J.; Yang, G.; Wu, C.; Huang, J. M.; Li, G.; Ma, D. L.; Leung, C. H. Small molecule Pin1 inhibitor blocking NF-kappaB signaling in prostate cancer cells. Chem. - Asian J. 2018, 13, 275– 279,  DOI: 10.1002/asia.201701216
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      Small Molecule Pin1 Inhibitor Blocking NF-κB Signaling in Prostate Cancer Cells
      Wu, Ke-Jia; Zhong, Hai-Jing; Yang, Guanjun; Wu, Chun; Huang, Jie-Min; Li, Guodong; Ma, Dik-Lung; Leung, Chung-Hang
      Chemistry - An Asian Journal (2018), 13 (3), 275-279CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Prolyl-isomerase 1 (Pin1) is a conserved enzyme that regulates cell processes such as cell cycle progression, transcriptional regulation, and apoptosis. However, overexpression of Pin1 is correlated with a higher probability of prostate tumor recurrence. The authors utilized a mol. docking technique to identify Pin1 inhibitors from a database of natural product and natural product-like compds. The action of the hit compds. against Pin1 activity was studied using multiple methods, including a fluorometric enzymic assay, co-immunopptn., western blotting, cell thermal shiftm, and other techniques. The authors have identified compd. 1 (I) as a natural-product-like inhibitor of Pin1 activity via structure-based virtual screening and showed that compd. 1 could target Pin1 and disrupt the interaction between Pin1 and the p65 subunit of NF-κB in cells. Furthermore, compd. 1 reduced nuclear p65 (Thr 254) phosphorylation and attenuated NF-κB activity in cells. Finally, compd. 1 induced apoptosis in prostate cancer cells. Compd. 1 represents a natural product-like Pin1 inhibitor that acts via targeting the Pin1-NF-κB interaction.
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      Wu, K. J.; Zhong, H. J.; Li, G.; Liu, C.; Wang, H. D.; Ma, D. L.; Leung, C. H. Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing. Eur. J. Med. Chem. 2018, 143, 1021– 1027,  DOI: 10.1016/j.ejmech.2017.11.101
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      Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing
      Wu, Ke-Jia; Zhong, Hai-Jing; Li, Guodong; Liu, Chenfu; Wang, Hui-Min David; Ma, Dik-Lung; Leung, Chung-Hang
      European Journal of Medicinal Chemistry (2018), 143 (), 1021-1027CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      NEDD8-activating enzyme (NAE) is an essential player of the NEDD8 conjugation pathway that regulates protein degrdn. Meanwhile, drug repurposing is a cost-efficient strategy to identify new therapeutic uses for existing scaffolds. In this report, mitoxantrone (1) was repurposed as an inhibitor of NAE by virtual screening of an FDA-approved drug database. Compd. 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity and was competitive with ATP. Furthermore, compd. 1 induced apoptosis of colorectal adenocarcinoma cancer cells through inhibiting the degrdn. of the neddylation substrate p53.
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      Nishanth, R. P.; Jyotsna, R. G.; Schlager, J. J.; Hussain, S. M.; Reddanna, P. Inflammatory responses of RAW 264.7 macrophages upon exposure to nanoparticles: role of ROS-NFkappaB signaling pathway. Nanotoxicology 2011, 5, 502– 516,  DOI: 10.3109/17435390.2010.541604
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      Inflammatory responses of RAW 264.7 macrophages upon exposure to nanoparticles: role of ROS-NFκB signaling pathway
      Nishanth, Reddy P.; Jyotsna, Radhika G.; Schlager, John J.; Hussain, Saber M.; Reddanna, Pallu
      Nanotoxicology (2011), 5 (4), 502-516CODEN: NANOGK; ISSN:1743-5404. (Informa Healthcare)
      Recent advances in particle-forming chemistries used for developing nanotechnol. has not only widened novel applications for nanoscale materials but also has provided significant concern regarding their biol. effects. The present study investigates the inflammatory responses of RAW 264.7 mouse macrophages exposed to nanoparticles (NPs, 5 μg/mL) of varied sizes including silver (Ag), aluminum (Al), carbon black (CB), carbon coated silver (CAg) and gold (Au). A significant increase in IL-6, reactive oxygen species (ROS) generation, nuclear translocation of nuclear factor-kappa B (NF-κB), induction of cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-α) expression was obsd. in macrophages with max. response found in cells exposed to Ag NPs followed by Al, CB and CAg. These pro-inflammatory effects of NPs were dependent on size and duration of exposure and comparable to those induced by lipopolysaccharide (LPS), a known inflammatory mediator. Au NPs, on the other hand, induced small but significant inflammatory responses in macrophages upon prolonged exposure. These studies reveal that Ag NPs exhibit higher propensity in inducing inflammation, mediated by ROS and NF-κB signaling pathways and leading to the induction of COX-2, TNF-α and IL-6. However, no such prominent pro-inflammatory responses were obsd. with Au NPs, suggesting their bio-compatibility.
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      Hsu, C. C.; Lien, J. C.; Chang, C. W.; Chang, C. H.; Kuo, S. C.; Huang, T. F. Yuwen02f1 suppresses LPS-induced endotoxemia and adjuvant-induced arthritis primarily through blockade of ROS formation, NFkB and MAPK activation. Biochem. Pharmacol. 2013, 85, 385– 395,  DOI: 10.1016/j.bcp.2012.11.002
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      Yuwen02f1 suppresses LPS-induced endotoxemia and adjuvant-induced arthritis primarily through blockade of ROS formation, NFkB and MAPK activation
      Hsu, Chun-Chieh; Lien, Jin-Cherng; Chang, Chia-Wen; Chang, Chien-Hsin; Kuo, Sheng-Chu; Huang, Tur-Fu
      Biochemical Pharmacology (Amsterdam, Netherlands) (2013), 85 (3), 385-395CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
      Phagocytes release inflammatory mediators to defense harmful stimuli upon bacterial invasion, however, excessive inflammatory reaction leads to tissue damage and manifestation of pathol. states. Therefore, targeting on uncontrolled inflammation seems feasible to control numerous inflammation-assocd. diseases. Under the drug screening process of synthetic diphenylpyrazole derivs., we discovered compd. yuwen02f1 possesses anti-inflammatory effects in decreasing the release of pro-inflammatory cytokines including TNFα and IL-6, nitric oxide, reactive oxygen species (ROS) as well as inhibiting migration of LPS-stimulated phagocytes. In addn., we obsd. that the mol. mechanism of yuwen02f1-mediated anti-inflammation is assocd. with decreasing phosphorylation of MAPK mols. including ERK1/2, JNK and p38, and attenuating translocation of p47phox and p67phox to the cell membrane. Yuwen02f1 also reverses IκBα degrdn. and attenuates the expression of NFκB-related downstream inducible enzymes like iNOS and COX-2. Furthermore, we found that yuwen02f1 attenuates some pathol. syndromes of LPS-induced sepsis and adjuvant-induced arthritis in mice, as evidenced by decreasing the cytokine prodn., reversing thrombocytopenic syndrome, protecting the mice from tissue injury in septic mice, and attenuating paw edema in arthritic mice as well. These results suggest that yuwen02f1 is a potential anti-inflammatory agent for alleviating syndromes of acute and chronic inflammatory diseases as evidenced by attenuating the generation of cytokines and down-regulating the expression of iNOS and COX-2 through the blockade of ROS generation and NADPH oxidase, NFκB and MAPK activation pathways in LPS-stimulated phagocytes.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslCnu7jK&md5=ed0d620f43912d7c37ec04cf5279cb72
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      Huang, Q.; Zhan, L.; Cao, H.; Li, J.; Lyu, Y.; Guo, X.; Zhang, J.; Ji, L.; Ren, T.; An, J.; Liu, B.; Nie, Y.; Xing, J. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy 2016, 12, 999– 1014,  DOI: 10.1080/15548627.2016.1166318
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      Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways
      Huang, Qichao; Zhan, Lei; Cao, Haiyan; Li, Jibin; Lyu, Yinghua; Guo, Xu; Zhang, Jing; Ji, Lele; Ren, Tingting; An, Jiaze; Liu, Bingrong; Nie, Yongzhan; Xing, Jinliang
      Autophagy (2016), 12 (6), 999-1014CODEN: AUTOC9; ISSN:1554-8635. (Taylor & Francis Ltd.)
      Mitochondrial morphol. is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, esp. in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying mol. mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS prodn. and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degrdn., and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a crit. role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.
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      Fan, R.; Bian, M.; Hu, L.; Liu, W. A new rhodium(I) NHC complex inhibits TrxR: In vitro cytotoxicity and in vivo hepatocellular carcinoma suppression. Eur. J. Med. Chem. 2019, 183, 111721,  DOI: 10.1016/j.ejmech.2019.111721
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      A new rhodium(I) NHC complex inhibits TrxR: In vitro cytotoxicity and in vivo hepatocellular carcinoma suppression
      Fan, Rong; Bian, Mianli; Hu, Lihong; Liu, Wukun
      European Journal of Medicinal Chemistry (2019), 183 (), 111721CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      Thioredoxin reductase (TrxR) is often overexpressed in different types of cancer cells including hepatocellular carcinoma (HCC) cells and regarded as a target with great promise for anticancer drug research and development. Here, we have synthesized and characterized nine new designed rhodium(I) N-heterocyclic carbene (NHC) complexes. All of them were effective towards cancer cells, esp. complex 1e was more active than cisplatin and manifested strong antiproliferative activity against HCC cells. In vivo anticancer studies showed that 1e significantly repressed tumor growth in an HCC nude mouse model and ameliorated liver lesions in a chronic HCC model caused by CCl4. Notably, a mechanistic study revealed that 1e can strongly inhibit TrxR system both in vitro and in vivo. Furthermore, 1e promoted intracellular ROS accumulation, damaged mitochondrial membrane potential, promoted cancer cell apoptosis and blocked the cells in the G1 phase.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVOltbzN&md5=221917adc043f7b4e42c3493996435e1
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      Huang, W.; Liu, Y.; Wang, J.; Yuan, X.; Jin, H. W.; Zhang, L. R.; Zhang, J. T.; Liu, Z. M.; Cui, J. R. Small-molecule compounds targeting the STAT3 DNA-binding domain suppress survival of cisplatin-resistant human ovarian cancer cells by inducing apoptosis. Eur. J. Med. Chem. 2018, 157, 887– 897,  DOI: 10.1016/j.ejmech.2018.08.037
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      Small-molecule compounds targeting the STAT3 DNA-binding domain suppress survival of cisplatin-resistant human ovarian cancer cells by inducing apoptosis
      Huang, Wei; Liu, Yuan; Wang, Jun; Yuan, Xia; Jin, Hong-Wei; Zhang, Liang-Ren; Zhang, Jian-Ting; Liu, Zhen-Ming; Cui, Jing-Rong
      European Journal of Medicinal Chemistry (2018), 157 (), 887-897CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      Constitutive activation of signal transducer and activator of transcription 3 (STAT3) plays important roles in oncogenic occurrence and transformation by regulating the expression of diverse downstream target genes important for tumor growth, metastasis, angiogenesis and immune evasion. Feasibility of targeting the DNA-binding domain (DBD) of STAT3 has been proven previously. With the aid of 3D shape- and electrostatic-based drug design, we identified a new STAT3 inhibitor, LC28, and its five analogs, based on the pharmacophore of a known STAT3 DBD inhibitor. Microscale thermophoresis assay shows that these compds. inhibits STAT3 binding to DNA with a Ki value of 0.74-8.87 μM. Furthermore, LC28 and its analogs suppress survival of cisplatin-resistant ovarian cancer cells by inhibiting STAT3 signaling and inducing apoptosis. Therefore, these compds. may serve as candidate compds. for further modification and development as anticancer therapeutics targeting the DBD of human STAT3 for treatment of cisplatin-resistant ovarian cancer.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsF2gtr3L&md5=43ff9b4ec08513e3b2b6196a438320ab
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      Bian, M.; Chen, X.; Zhang, C.; Jin, H.; Wang, F.; Shao, J.; Chen, A.; Zhang, F.; Zheng, S. Magnesium isoglycyrrhizinate promotes the activated hepatic stellate cells apoptosis via endoplasmic reticulum stress and ameliorates fibrogenesis in vitro and in vivo. Biofactors 2017, 43, 836– 846,  DOI: 10.1002/biof.1390
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      Magnesium isoglycyrrhizinate promotes the activated hepatic stellate cells apoptosis via endoplasmic reticulum stress and ameliorates fibrogenesis in vitro and in vivo
      Bian, Mianli; Chen, Xingran; Zhang, Chenxi; Jin, Huanhuan; Wang, Feixia; Shao, Jiangjuan; Chen, Anping; Zhang, Feng; Zheng, Shizhong
      BioFactors (2017), 43 (6), 836-846CODEN: BIFAEU; ISSN:1872-8081. (Wiley-Blackwell)
      Varied pathogenetic elements have been touched upon the liver fibrosis, including inflammatory, stress, apoptosis and unfolded proteins aggregation. Magnesium Isoglycyrrhizinate (MgIG) has been accepted to be a neuroprotective effect, hepatoprotective and anti-inflammatory mol. In our vitro researches, MgIG was considered to activate hepatic stellate cells (HSCs) apoptosis by promoting endoplasmic reticulum stress (ERS) detrimental response to a certain extent. Consequently, MgIG showed its potential therapeutic capacity in fibrogenesis and counteracted the pathogenetic aspects, which were involved in integrating current treatments correcting liver fibrosis. In addn., we further verificated the behavior and pathogenic mechanisms in the CCl4-induced liver fibrosis in male mice. What surprised us was that with the treatment of MgIG caused the activation of ERS and resisted the activated HSCs in the protective effects on liver damage. We found MgIG significantly promoted the apoptosis of activated HSCs and protected the CCl4-induced liver fibrosis. Main mols. came down to the unfolded protein response signaling pathway. Furthermore, MgIG inhibited the levels of the downstream inflammatory cytokines, which were triggered by CCl4-induced liver fibrosis. Here, we reported that MgIG improved behavioral impairments induced by i.p. injection of CCl4 and decreased the expression of proinflammatory factor, which indicated the preserving effects on liver fibrosis. © 2017 BioFactors, 2017.
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      Raoof, M.; Corr, S. J.; Zhu, C.; Cisneros, B. T.; Kaluarachchi, W. D.; Phounsavath, S.; Wilson, L. J.; Curley, S. A. Gold nanoparticles and radiofrequency in experimental models for hepatocellular carcinoma. Nanomedicine 2014, 10, 1121– 1130,  DOI: 10.1016/j.nano.2014.03.004
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      Gold nanoparticles and radiofrequency in experimental models for hepatocellular carcinoma
      Raoof, Mustafa; Corr, Stuart J.; Zhu, Cihui; Cisneros, Brandon T.; Kaluarachchi, Warna D.; Phounsavath, Sophia; Wilson, Lon J.; Curley, Steven A.
      Nanomedicine (New York, NY, United States) (2014), 10 (6), 1121-1130CODEN: NANOBF; ISSN:1549-9634. (Elsevier)
      Hepatocellular carcinoma (HCC) is one of the most lethal and chemo-refractory cancers, clearly, alternative treatment strategies are needed. We utilized 10 nm gold nanoparticles as a scaffold to synthesize nanoconjugates bearing a targeting antibody (cetuximab, C225) and gemcitabine. Loading efficiency of gemcitabine on the gold nanoconjugates was 30%. Targeted gold nanoconjugates in combination with RF were selectively cytotoxic to EGFR expressing Hep3B and SNU449 cells when compared to isotype particles with/without RF (P < 0.05). In animal expts., targeted gold nanoconjugates halted the growth of s.c. Hep3B xenografts in combination with RF exposure (P < 0.05). These xenografts also demonstrated increased apoptosis, necrosis and decreased proliferation compared to controls. Normal tissues were unharmed. We have demonstrated that non-invasive RF-induced hyperthermia when combined with targeted delivery of gemcitabine is more effective and safe at dosages ∼ 275-fold lower than the current clin.-delivered systemic dose of gemcitabine.In a model of hepatocellular carcinoma, the authors demonstrate that non-invasive RF-induced hyperthermia applied with cetuximab targeted delivery of Au NP-gemcitabine conjugate is more effective and safe at dosages ∼ 275-fold lower than the current clin.-used systemic dose of gemcitabine.
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      Newell, P.; Villanueva, A.; Friedman, S. L.; Koike, K.; Llovet, J. M. Experimental models of hepatocellular carcinoma. J. Hepatol. 2008, 48, 858– 879,  DOI: 10.1016/j.jhep.2008.01.008
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      Experimental models of hepatocellular carcinoma
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      Journal of Hepatology (2008), 48 (5), 858-879CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)
      A review. Hepatocellular carcinoma (HCC) is a common and deadly cancer whose pathogenesis is incompletely understood. Comparative genomic studies from human HCC samples have classified HCCs into different mol. subgroups; yet, the unifying feature of this tumor is its propensity to arise upon a background of inflammation and fibrosis. This review seeks to analyze the available exptl. models in HCC research and to correlate data from human populations with them in order to consolidate our efforts to date, as it is increasingly clear that different models will be required to mimic different subclasses of the neoplasm. These models will be instrumental in the evaluation of compds. targeting specific mol. pathways in future preclin. studies.
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      Reyes-Gordillo, K.; Shah, R.; Arellanes-Robledo, J.; Cheng, Y.; Ibrahim, J.; Tuma, P. L. Akt1 and Akt2 isoforms play distinct roles in regulating the development of inflammation and fibrosis associated with alcoholic liver disease. Cells 2019, 8, 1337,  DOI: 10.3390/cells8111337
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      Akt1 and Akt2 isoforms play distinct roles in regulating the development of inflammation and fibrosis associated with alcoholic liver disease
      Reyes-Gordillo, Karina; Shah, Ruchi; Arellanes-Robledo, Jaime; Cheng, Ying; Ibrahim, Joseph; Tuma, Pamela L.
      Cells (2019), 8 (11), 1337CODEN: CELLC6; ISSN:2073-4409. (MDPI AG)
      Akt kinase isoforms (Akt1, Akt2, and Akt3) have generally been thought to play overlapping roles in phosphoinositide 3-kinase (PI3K)-mediated-signaling. However, recent studies have suggested that they display isoform-specific roles in muscle and fat. To det. whether such isoform-specificity is obsd. with respect to alc. liver disease (ALD) progression, we examd. the role of Akt1, Akt2, and Akt3 in hepatic inflammation, and pro-fibrogenic proliferation and migration using Kupffer cells, hepatic stellate cells (HSC), and hepatocytes in an ethanol and lipopolysaccharide (LPS)-induced two-hit model in vitro and in vivo. We detd. that siRNA-directed silencing of Akt2, but not Akt1, significantly suppressed cell inflammatory markers in HSC and Kupffer cells. Although both Akt1 and Akt2 inhibited cell proliferation in HSC, only Akt2 inhibited cell migration. Both Akt1 and Akt2, but not Akt3, inhibited fibrogenesis in hepatocytes and HSC. In addn., our in vivo results show that administration of chronic ethanol, binge ethanol and LPS (EBL) in wild-type C57BL/6 mice activated all three Akt isoforms with concomitant increases in activated forms of phosphoinositide dependent kinase-1 (PDK1), mammalian target-of-rapamycin complex 2 (mTORC2), and PI3K, resulting in upregulation in expression of inflammatory, proliferative, and fibrogenic genes. Moreover, pharmacol. blocking of Akt2, but not Akt1, inhibited EBL-induced inflammation while blocking of both Akt1 and Akt2 inhibited pro-fibrogenic marker expression and progression of fibrosis. Our findings indicate that Akt isoforms play unique roles in inflammation, cell proliferation, migration, and fibrogenesis during EBL-induced liver injury. Thus, close attention must be paid when targeting all Akt isoforms as a therapeutic intervention.
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      Pawlak, M.; Lefebvre, P.; Staels, B. Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J. Hepatol. 2015, 62, 720– 733,  DOI: 10.1016/j.jhep.2014.10.039
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      Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease
      Pawlak, Michal; Lefebvre, Philippe; Staels, Bart
      Journal of Hepatology (2015), 62 (3), 720-733CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)
      Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor belonging, together with PPARγ and PPARβ/δ, to the NR1C nuclear receptor subfamily. Many PPARα target genes are involved in fatty acid metab. in tissues with high oxidative rates such as muscle, heart and liver. PPARα activation, in combination with PPARβ/δ agonism, improves steatosis, inflammation and fibrosis in pre-clin. models of non-alc. fatty liver disease, identifying a new potential therapeutic area. In this review, we discuss the transcriptional activation and repression mechanisms by PPARα, the spectrum of target genes and chromatin-binding maps from recent genome-wide studies, paying particular attention to PPARα-regulation of hepatic fatty acid and plasma lipoprotein metab. during nutritional transition, and of the inflammatory response. The role of PPARα, together with other PPARs, in non-alc. steatohepatitis will be discussed in light of available pre-clin. and clin. data.
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    57. 57
      Zhou, H.; Yu, M.; Zhao, J.; Martin, B. N.; Roychowdhury, S.; McMullen, M. R.; Wang, E.; Fox, P. L.; Yamasaki, S.; Nagy, L. E.; Li, X. IRAKM-Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease. Hepatology 2016, 64, 1978– 1993,  DOI: 10.1002/hep.28811
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      IRAKM-Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease
      Zhou, Hao; Yu, Minjia; Zhao, Junjie; Martin, Bradley N.; Roychowdhury, Sanjoy; McMullen, Megan R.; Wang, Emily; Fox, Paul L.; Yamasaki, Sho; Nagy, Laura E.; Li, Xiaoxia
      Hepatology (Hoboken, NJ, United States) (2016), 64 (6), 1978-1993CODEN: HPTLD9; ISSN:0270-9139. (John Wiley & Sons, Inc.)
      Lipopolysaccharide (LPS)-mediated activation of Toll-like receptors (TLRs) in hepatic macrophages and injury to hepatocytes are major contributors to the pathogenesis of alc. liver disease. However, the mechanisms by which TLR-dependent inflammatory responses and alc.-induced hepatocellular damage coordinately lead to alc. liver disease are not completely understood. In this study, we found that mice deficient in interleukin-1 receptor-assocd. kinase M (IRAKM), a proximal TLR pathway mol. typically assocd. with inhibition of TLR signaling, were actually protected from chronic ethanol-induced liver injury. In bone marrow-derived macrophages challenged with low concns. of LPS, which reflect the relevant pathophysiol. levels of LPS in both alc. patients and ethanol-fed mice, the IRAKM Myddosome was preferentially formed. Further, the IRAKM Myddosome mediated the up-regulation of Mincle, a sensor for cell death. Mincle-deficient mice were also protected from ethanol-induced liver injury. The endogenous Mincle ligand spliceosome-assocd. protein 130 (SAP130) is a danger signal released by damaged cells; culture of hepatocytes with ethanol increased the release of SAP130. Ex vivo studies in bone marrow-derived macrophages suggested that SAP130 and LPS synergistically activated inflammatory responses, including inflammasome activation. Conclusion: This study reveals a novel IRAKM-Mincle axis that contributes to the pathogenesis of ethanol-induced liver injury.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvV2gsbrE&md5=ec473a4ed74fec67396c854401e1dcd0
    58. 58
      Bian, M.; He, J.; Jin, H.; Lian, N.; Shao, J.; Guo, Q.; Wang, S.; Zhang, F.; Zheng, S. Oroxylin A induces apoptosis of activated hepatic stellate cells through endoplasmic reticulum stress. Apoptosis 2019, 24, 905– 920,  DOI: 10.1007/s10495-019-01568-2
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      Oroxylin A induces apoptosis of activated hepatic stellate cells through endoplasmic reticulum stress
      Bian, Mianli; He, Jianlin; Jin, Huanhuan; Lian, Naqi; Shao, Jiangjuan; Guo, Qinglong; Wang, Shijun; Zhang, Feng; Zheng, Shizhong
      Apoptosis (2019), 24 (11-12), 905-920CODEN: APOPFN; ISSN:1360-8185. (Springer)
      Hepatic stellate cell (HSC) activation plays an indispensable role in hepatic fibrosis. Inducing apoptosis of activated HSCs can attenuate or reverse fibrogenesis. In this study, the initial find that oroxylin A (OA) protected CCl4-induced liver injury accompanied by endoplasmic reticulum stress (ERS) activation of HSCs in mice. In vitro, OA treatment markedly reduced fibrogenesis by modulating extracellular matrix synthesis and degrdn. OA inhibited cell proliferation and induced cell cycle arrest of HSCs at S phase. Further, OA was obsd. to induce HSC apoptosis, as indicated by caspase activation. Using the eIF2α dephosphorylation inhibitor salubrinal, we found that ERS pathway activation was required for OA to induce HSC apoptosis. ERS-related proteins were significantly upregulated by OA treatment, and salubrinal abrogated the effects of OA on HSCs. Thus, They inferred that OA attenuated HSC activation by promoting ERS. In vivo, inhibition of ERS by salubrinal partly abrogated the hepatoprotective effect of OA in CCl4-treated mice. In conclusion, our findings suggest a role for ERS in the mechanism underlying amelioration of hepatic fibrosis by OA.
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