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Comparative cytotoxicity of auranofin and other gold compounds (A) and classical chemotherapeutic agents (B) on cell growth of A2780 and A2780/AF-R cells. Data are means ± standard error derived from at least three independent 72-h drug exposure experiments. CRI, cross-resistance index; *p<0.001; **p≤0.05.
Source publication
The anti-arthritic drug auranofin exerts also potent antitumour activity in in vitro and in vivo models, whose mechanisms are not yet well defined. From an auranofin-sensitive human ovarian cancer cell line A2780, a highly resistant (>20-fold) subline (A2780/AF-R) was developed and characterized. Marked reduction of gold accumulation occurred in au...
Contexts in source publication
Context 1
... Au 2 Phen 2 was more active, on a micromolar basis, than auranofin. In the sensitive cell line the relative degree of cytotoxicity was Au 2 Phen 2 >auranofin>Au(NHC) 2 >Au( NHC)Cl>Auoxo6>Aubipy c >AuL12 (most to least active) ( Figure 2A). ...
Context 2
... latter compounds were able to completely circumvent resistance to auranofin (CRI <1.5) (Figure 2A). ...
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Citations
... However, such studies were conducted using cell lines that do not represent the high-grade serous histotype we report here. For instance, studies have used A2780 cells [17,18], which have been identified as representing an endometrial ovarian carcinoma [19]; OV2008 [20], which have been reported to be misidentified [21] and likely of a cervical nature [22]; SKOV-3 [23,24], which have been genetically identified to represent a clear ovarian adenocarcinoma [19]; and OVCAR-5 [24], which were incorrectly identified as being of ovarian origin while they are actually of a gastrointestinal nature [25]. Finally, other studies have used the platinum-resistant OV2008 (C13*) [20,26], which are cells that were developed in vitro from OV2008 cells after a dose-escalating exposure to cisplatin. ...
... The cytotoxic properties of auranofin as a monotherapy or in combination with oth drugs have been studied in various cancers, including lung [47][48][49][50], breast [51][52][53], p creatic adenocarcinoma [36], colorectal [54], gastric [55], mesothelioma [34], melano [56], malignant B-cells, and acute lymphoblastic leukaemia (ALL) [57][58][59]. In ovarian c cer, auranofin has been shown to block the growth of A2780, SKOV-3, and IGROV-1 ce [17,20,24,38,60], but none of these cell lines represent the most common histotype wh is HGSOC [19,61]. In our study, we used two cell types, PEO1 (platinum sensitive) a PEO4 (platinum resistant), which were isolated from the same patient throughout course of the disease [27] and genotypically identified as HGSOC [28]. ...
... The cytotoxic properties of auranofin as a monotherapy or in combination with other drugs have been studied in various cancers, including lung [47][48][49][50], breast [51][52][53], pancreatic adenocarcinoma [36], colorectal [54], gastric [55], mesothelioma [34], melanoma [56], malignant B-cells, and acute lymphoblastic leukaemia (ALL) [57][58][59]. In ovarian cancer, auranofin has been shown to block the growth of A2780, SKOV-3, and IGROV-1 cells [17,20,24,38,60], but none of these cell lines represent the most common histotype which is HGSOC [19,61]. In our study, we used two cell types, PEO1 (platinum sensitive) and PEO4 (platinum resistant), which were isolated from the same patient throughout the course of the disease [27] and genotypically identified as HGSOC [28]. ...
Simple Summary
High-grade serous ovarian cancer (HGSOC) is the most prevalent type of ovarian cancer, accounting for 70% of ovarian cancer deaths. This is primarily due to the development of resistance against standard platinum-based chemotherapy. Several drugs are currently undergoing repurposing against ovarian cancer, including auranofin (AF), an anti-rheumatoid agent. The mechanism of action of AF has been studied in various cancers, however, there have been fewer studies on the effects of AF in HGSOC. In this study, we explore the mechanisms of action of AF in human HGSOC cells that are sensitive or resistant to platinum. We demonstrate the various cytotoxic effects of AF in HGSOC via the targeting of multiple pathways, suggesting the potential use of AF in a long-term consolidation therapy against this disease.
Abstract
High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases, and the survival rate remains remarkably low due to the lack of effective long-term consolidation therapies. Clinical remission can be temporarily induced by platinum-based chemotherapy, but death subsequently results from the extensive growth of a platinum-resistant component of the tumor. This work explores a novel treatment against HGSOC using the gold complex auranofin (AF). AF primarily functions as a pro-oxidant by inhibiting thioredoxin reductase (TrxR), an antioxidant enzyme overexpressed in ovarian cancer. We investigated the effect of AF on TrxR activity and the various mechanisms of cytotoxicity using HGSOC cells that are clinically sensitive or resistant to platinum. In addition, we studied the interaction between AF and another pro-oxidant, L-buthionine sulfoximine (L-BSO), an anti-glutathione (GSH) compound. We demonstrated that AF potently inhibited TrxR activity and reduced the vitality and viability of HGSOC cells regardless of their sensitivities to platinum. We showed that AF induces the accumulation of reactive oxygen species (ROS), triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis. Notably, AF-induced cell death was abrogated by the ROS-scavenger N-acetyl cysteine (NAC). In addition, the lethality of AF was associated with the activation of caspases-3/7 and the generation of DNA damage, effects that were also prevented by the presence of NAC. Finally, when AF and L-BSO were combined, we observed synergistic lethality against HGSOC cells, which was mediated by a further increase in ROS and a decrease in the levels of the antioxidant GSH. In summary, our results support the concept that AF can be used alone or in combination with L-BSO to kill HGSOC cells regardless of their sensitivity to platinum, suggesting that the depletion of antioxidants is an efficient strategy to mitigate the course of this disease.
... In fact, they are special objects that have little in common with other gold(III) complexes. Another direction is highly stable gold(I) complexes with phosphine ligands R'SAuPR 3 (Shaw III 1999;Bryan et al. 1987;Roberts et al. 1996;Keter et al. 2014;Kim et al. 2019;Landini et al. 2017;Walz et al. 1983). Among them, auranofin, which also exhibits high antitumor activity, has been studied in the most detail. ...
Gold(III) complexes are widely studied as antitumor agents and show good results. The interaction with biologically active thiols (thiomalate, cysteine, glutathione (GSH) and human serum albumin) of a number of gold(III) complexes with N-containing polydentate ligands in aqueous solution with pH 7.4 and 0.2 M NaCl was studied. Complexes with 1,10-phenanthroline and 2,2′-bipyridyl, Au(phen)(OH)2⁺ and Au(bipy)(OH)2⁺, react fast with an excess of any of these thiols and in less than a few seconds transform into gold(I) bis-thiolate complexes. For complexes with deprotonated ethylenediamine and diethylenetriamine, Au(en)(en-H)²⁺ and Au(dien-H)(Cl,OH)⁺, at a significant excess of GSH, a relatively long-lived gold(III) complex AuIII(GSH)iLj is formed. At t = 37 °C, it transforms into the gold(I) bis-thiolate complex Au(GSH)2 by 90% in 4 h. However, for other thiols, the rate of decomposition of similar complexes is about 10 times higher. Some other complexes were also considered. In all cases, a fairly fast reduction of gold(III) to gold(I) occurs with the formation of the gold(I) bis-thiolates.
... Mechanisms of cytotoxicity of auranofin as a monotherapy or in combination with other drugs have been studied in various cancers including lung [38][39][40][41], breast [42][43][44] [46], mesothelioma [47], melanoma cells [48], malignant B-cells and acute lymphoblastic leukaemia (ALL) [49][50][51]. In ovarian cancer, auranofin has been shown to be efficient in blocking the growth of A2780, SKOV-3, OVCAR-5, IGROV-1, and OV2008 cells [20,27,[52][53][54]. However, despite popular, all these cell lines are unlikely to represent the most common histotype of ovarian cancer we study in this manuscript: ...
High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases in the clinical setting; the survival rate for this disease remains remarkably low due to the lack of long-term consolidation therapies following the standard platinum-based chemotherapy, which is not long lasting as the disease recurs as platinum resistant. The purpose of this study was to explore a novel treatment against HGSOC using the gold complex auranofin (AF). AF primarily functions as a pro-oxidant agent through the inhibition of thioredoxin reductase (TrxR), an antioxidant enzyme that is overexpressed in ovarian cancer. We investigated the effect of AF on TrxR activity and various mechanisms of cytotoxicity using HGSOC cells that are clinically sensitive or resistant to platinum. In addition, we studied the interaction between AF and another pro-oxidant agent, L-buthionine sulfoximine (L-BSO), an anti-glutathione (GSH) compound. We demonstrate that AF potently inhibits TrxR activity and reduces the vitality and viability of HGSOC cells regardless of their sensitivities to platinum. We show that AF induces accumulation of reactive oxygen species (ROS), triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis. Yet, AF-induced cell death is abrogated by the ROS-scavenger N-acetyl cysteine (NAC). In addition, the lethality of AF is associated with the activation of caspases-3/7 and the generation of DNA damage, effects that are also prevented by the presence of NAC. Finally, when AF and L-BSO are combined, we observed a synergistic lethality against HGSOC cells, which is mediated by a further increase in ROS together with a decrease in the levels of the antioxidant GSH. In summary, our results support the concept that AF can be used alone or in combination with L-BSO to kill HGSOC cells regardless of their platinum sensitivities suggesting that depletion of antioxidants is an efficient route for treating this disease.
... As shown in Figure 9, Ctr1, OCT1, and OCT2 were lower in A2780cisR than in A2780, whereas OCT3 was signifcantly higher. Tis scenario is not very diferent from that found for the expression of A2780 cells made resistant to the Au-based metal-drug auranofn [104]. Tis behavior suggests a role for OCT3 in the transport of 2 in A2780cisR. ...
The biological behavior of the axially unsymmetric antitumor prodrug (OC-6-44)-acetatodiamminedichloridohydroxidoplatinum(IV), 2, was deeply investigated and compared with that of analogous symmetric Pt(IV) complexes, namely, dihydroxido 1 and diacetato 3, which have a similar structure. The complexes were tested on a panel of human tumor cell lines. Complex 2 showed an anomalous higher cytotoxicity (similar to that of cisplatin) with respect to their analogues 1 and 3. Their reduction potentials, reduction kinetics, lipophilicity, and membrane affinity are compared. Cellular uptake and DNA platination of Pt(IV) complexes were deeply investigated in the sensitive A2780 human ovarian cancer cell line and in the corresponding resistant A2780cisR subline. The unexpected activity of 2 appears to be related to its peculiar cellular accumulation and not to a different rate of reduction or a different efficacy in DNA platination and/or efficiency in apoptosis induction. Although the exact mechanism of cell uptake is not fully deciphered, a series of naïve experiments indicates an energy-dependent, carrier-mediated transport: the organic cation transporters (OCTs) are the likely proteins involved.
... Concentrations in both phases were determined through ICP-AES, following a well-established mineralisation protocol. 68 The reported log P value is defined as log 10 ...
A novel gold(I) complex inspired by the known medicinal inorganic compounds auranofin and thimerosal, namely ethylthiosalicylate(triethylphosphine)gold(I) (AFETT hereafter), was synthesized and characterised and its structure was resolved through X-ray diffraction. The solution behavior of AFETT and its interactions with two biologically relevant proteins (i.e. human serum albumin and haemoglobin) and with a synthetic dodecapeptide reproducing the C-terminal portion of thioredoxin reductase were comparatively analyzed through 31P NMR and ESI-MS. Remarkable binding properties toward these biomolecules were disclosed. Moreover, the cytotoxic effects produced by AFETT on two ovarian cancer cell lines (A2780 and A2780 R) and one colorectal cancer cell line (HCT116) were analyzed and found to be strong and nearly superimposable to those of auranofin. Interestingly, for both compounds, the ability to induce downregulation of vimentin expression in A2780 R cells was evidenced. Despite its close similarity to auranofin, AFETT is reported to exhibit some peculiar and distinctive features such as a lower lipophilicity, an increased water solubility and a faster reactivity towards the selected target biomolecules. These differences might confer to AFETT significant pharmaceutical and therapeutic advantages over auranofin itself.
... Gold(III) complexes with nitrogen-containing ligands have recently attracted considerable attention [1][2][3][4]. This is due to the results of numerous studies showing that these complexes exhibit antitumor properties and are often superior in this respect to platinum(II) compounds [5][6][7][8]. A characteristic example is gold(III) complexes with 1,10-phenanthroline (phen) and its derivatives. ...
Phenanthroline complexes of gold(III) are widely studied as antitumor agents. In this work, we use Au(phen)(Formula presented.) (X = Cl or OH) as an example to study two most important processes accompanying the use of these complexes, namely, the equilibrium of Cl– substitution by OH– and redox interaction with glutathione (GSH) in an aqueous solution at T = 25°C and I = 0.2 M (NaCl). The equilibrium Au(phen)(Formula presented.) + iOH– = Au(phen)Cl2 –i(Formula presented.) has log βi = 8.39 (i = 1) and 15.41 (i = 2). Au(phen)(Formula presented.) reduction by GSH proceeds rapidly. The major reduction products are highly stable gold(I) complexes, namely, polymeric (AuGSHi)m and Au(GSHi)2. When GSH is in deficit, the major end product of its oxidation is sulfonic acid GSO3H; when it is in excess, the end product is disulfide GSSG. An excess of phen does not affect the redox process. The reaction of (Formula presented.) with phen in aqueous solution leads to rapid disproportionation with release of gold(0).
... Biphasic solutions were mixed for 10 minutes and then centrifuged at 25 • C for 5 min at 6000 rpm to allow separation. Concentrations in both phases were determined through ICP-AES, following an already published mineralization protocol [55]. The reported log LogP value is defined as log10([complex] oct /[complex] wat ). ...
Auranofin (AF, hereafter) is an orally administered chrysotherapeutic agent approved for the treatment of rheumatoid arthritis that is being repurposed for various indications including bacterial infections. Its likely mode of action involves the impairment of the TrxR system through the binding of the pharmacophoric cation [AuPEt3]+. Accordingly, a reliable strategy to expand the medicinal profile of AF is the replacement of the thiosugar moiety with different ligands. Herein, we aimed to prepare the AF analogue bearing the acetylcysteine ligand (AF-AcCys, hereafter) and characterize its anti-staphylococcal activity. Biological studies revealed that AF-AcCys retains an antibacterial effect superimposable with that of AF against Staphylococcus aureus, whereas it is about 20 times less effective against Staphylococcus epidermidis. Bioinorganic studies confirmed that upon incubation with human serum albumin, AF-AcCys, similarly to AF, induced protein metalation through the [AuPEt3]+ fragment. Additionally, AF-AcCys appeared capable of binding the dodecapeptide Ac-SGGDILQSGCUG-NH2, corresponding to the tryptic C-terminal fragment (488–499) of hTrxR. To shed light on the pharmacological differences between AF and AF-AcCys, we carried out a comparative experimental stability study and a theoretical estimation of bond dissociation energies, unveiling the higher strength of the Au–S bond in AF-AcCys. From the results, it emerged that the lower lipophilicity of AF-AcCys with respect to AF could be a key feature for its different antibacterial activity. The differences and similarities between AF and AF-AcCys are discussed, alongside the opportunities and consequences that chemical structure modifications imply.
... Biphasic solutions were mixed for 10 minutes and then centrifuged at 25 • C for 5 min at 6000 rpm to allow separation. Concentrations in both phases were determined through ICP-AES, following an already published mineralization protocol [55]. The reported log LogP value is defined as log10([complex] oct /[complex] wat ). ...
Auranofin (AF, hereafter) is an orally administered chrysotherapeutic agent approved for the treatment of rheumatoid arthritis that is being repurposed for various indications including bacterial infections. Its likely mode of action involves the impairment of the TrxR system through the binding of the pharmacophoric cation [AuPEt3]+. Accordingly, a reliable strategy to expand the medicinal profile of AF is the replacement of the thiosugar moiety with different ligands. Herein, we aimed to prepare the AF analogue bearing the acetylcysteine ligand (AF-AcCys, hereafter) and characterize its anti-staphylococcal activity. Biological studies revealed that AF-AcCys retains an antibacterial effect superimposable with that of AF against Staphylococcus aureus, whereas it is about 20 times less effective against Staphylococcus epidermidis. Bioinorganic studies confirmed that upon incubation with human serum albumin, AF-AcCys, similarly to AF, induced protein metalation through the [AuPEt3]+ fragment. Additionally, AF-AcCys appeared capable of binding the dodecapeptide Ac-SGGDILQSGCUG-NH2, corresponding to the tryptic C-terminal fragment (488–499) of hTrxR. To shed light on the pharmacological differences between AF and AF-AcCys, we carried out a comparative experimental stability study and a theoretical estimation of bond dissociation energies, unveiling the higher strength of the Au–S bond in AF-AcCys. From the results, it emerged that the lower lipophilicity of AF-AcCys with respect to AF could be a key feature for its different antibacterial activity. The differences and similarities between AF and AF-AcCys are discussed, alongside the opportunities and consequences that chemical structure modifications imply.
... Identifier: NCT03456700). Landini et al. characterized an AF-resistant ovarian cancer cell line and reported that the alteration of gold uptake mediated by the organic cation/anion efflux system could be one of the mechanisms underlying the drug resistance [94]. Besides the expected cell death mechanisms involving the canonical intrinsic apoptosis pathway, the present study revealed some interesting details of the ovarian cancer cell adaptative response to AF treatment. ...
The effects of Auranofin (AF) on protein expression and protein oxidation in A2780 cancer cells were investigated through a strategy based on simultaneous expression proteomics and redox proteomics determinations. Bioinformatics analysis of the proteomics data supports the view that the most critical cellular changes elicited by AF treatment consist of thioredoxin reductase inhibition, alteration of the cell redox state, impairment of the mitochondrial functions, metabolic changes associated with conversion to a glycolytic phenotype, induction of ER stress. The occurrence of the above cellular changes was extensively validated by performing direct biochemical assays. Our data are consistent with the concept that AF produces its effects through a multitarget mechanism that mainly affects the redox metabolism and the mitochondrial functions and results into severe ER stress. Results are discussed in the context of the current mechanistic knowledge existing on AF.
... Of interest, cancer cells can develop resistance to auranofin by reduced drug accumulation caused by the dysregulation of influx and efflux drug transporters, as demonstrated in ovarian cancer cells that were made approximately 20-fold resistant to the gold I complex upon stepwise exposure of a parental cell line to increasing auranofin concentrations during an 8-month selection period [98]. The development of resistance to auranofin seems to be very specific as the resistant cells retained sensitivity to other investigational gold compounds, as well as to approved chemotherapeutics such as oxaliplatin, vinblastine, doxorubicin, etoposide, and paclitaxel [98]. ...
... Of interest, cancer cells can develop resistance to auranofin by reduced drug accumulation caused by the dysregulation of influx and efflux drug transporters, as demonstrated in ovarian cancer cells that were made approximately 20-fold resistant to the gold I complex upon stepwise exposure of a parental cell line to increasing auranofin concentrations during an 8-month selection period [98]. The development of resistance to auranofin seems to be very specific as the resistant cells retained sensitivity to other investigational gold compounds, as well as to approved chemotherapeutics such as oxaliplatin, vinblastine, doxorubicin, etoposide, and paclitaxel [98]. ...
Advanced stages of cancer are highly associated with short overall survival in patients due to the lack of long-term treatment options following the standard form of care. New options for cancer therapy are needed to improve the survival of cancer patients without disease recurrence. Auranofin is a clinically approved agent against rheumatoid arthritis that is currently enrolled in clinical trials for potential repurposing against cancer. Auranofin mainly targets the anti-oxidative system catalyzed by thioredoxin reductase (TrxR), which protects the cell from oxidative stress and death in the cytoplasm and the mitochondria. TrxR is over-expressed in many cancers as an adaptive mechanism for cancer cell proliferation, rendering it an attractive target for cancer therapy, and auranofin as a potential therapeutic agent for cancer. Inhibiting TrxR dysregulates the intracellular redox state causing increased intracellular reactive oxygen species levels, and stimulates cellular demise. An alternate mechanism of action of auranofin is to mimic proteasomal inhibition by blocking the ubiquitin–proteasome system (UPS), which is critically important in cancer cells to prevent cell death when compared to non-cancer cells, because of its role on cell cycle regulation, protein degradation, gene expression, and DNA repair. This article provides new perspectives on the potential mechanisms used by auranofin alone, in combination with diverse other compounds, or in combination with platinating agents and/or immune checkpoint inhibitors to combat cancer cells, while assessing the feasibility for its repurposing in the clinical setting.
