Auranofin induces mesothelioma cell death through oxidative stress and GSH depletion

You, Bo; Park, Woo Hyun

doi:10.3892/or.2015.4382

Cited by 42 publications

(41 citation statements)

References 30 publications

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“…The inhibition of DNA replication by auranofin is not an important factor for inducing cytotoxicity, 14) and its direct interaction with DNA also does not contribute to its cytotoxicity. 15) Auranofin induces apoptosis in several cancer cell lines by increasing the level of reactive oxygen species (ROS) and changing the cellular redox state. 16) Interestingly, in tumor cells, auranofin inhibits the deubiquitinating enzyme associated with the 19S regulatory subunits of proteasomes, consequently inducing apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…15) Auranofin induces apoptosis in several cancer cell lines by increasing the level of reactive oxygen species (ROS) and changing the cellular redox state. 16) Interestingly, in tumor cells, auranofin inhibits the deubiquitinating enzyme associated with the 19S regulatory subunits of proteasomes, consequently inducing apoptosis. 17,18) Auranofin may interact with several intracellular proteins causing cell proliferation and inhibition of the signaling pathways involved in cancer progression.…”

Section: Introductionmentioning

confidence: 99%

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Potential Anticancer Activity of Auranofin

2019

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Gold compounds have a long history of use in medicine. Auranofin was developed more than 30 years ago as an oral therapy for rheumatoid arthritis. Now, however, auranofin is rarely used in clinical practice despite its efficacy for treating rheumatoid arthritis because more novel antirheumatic medications are available. Although its use in clinical practice has decreased, studies on auranofin have continued and it shows promise for the treatment of several different diseases, including cancer and bacterial and parasitic infections. Several potential novel applications of auranofin for treating human disease have been proposed. Auranofin inhibits the activity of thioredoxin reductase (TrxR), an enzyme of the thioredoxin (Trx) system that is important for maintaining the intracellular redox state. Particularly in cancers, TrxR inhibition leads to an increase in cellular oxidative stress and induces apoptosis. TrxR overexpression is associated with aggressive tumor progression and poor survival in patients with breast, ovarian, and lung cancers. The Trx system may represent an attractive target for the development of new cancer treatments. Therefore, the TrxR inhibitor auranofin may be a potent anticancer agent. This review summarizes the current understanding of auranofin for cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potential Anticancer Activity of Auranofin

2019

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“…Trypanothione reductase of L. infantum (Ilari et al, 2012) revealed, albeit at low resolution, evidence for Auranofin’s tetra-acetyl-thio-glucopyranoside moiety binding to the trypanothione binding site, suggesting interference with the substrate as another possible mechanism of inhibition. Dual inhibition of inflammatory and redox pathways by Auranofin makes it a promising candidate for new applications as an anti-cancer agent (Li et al, 2015; Topkas et al, 2015; You and Park, 2015) and in treating of parasitic infections in humans (Debnath et al, 2012a; Madeira et al, 2012; Tejman-Yarden et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

X-ray structures of thioredoxin and thioredoxin reductase from Entamoeba histolytica and prevailing hypothesis of the mechanism of Auranofin action

Parsonage

Sheng

Hirata

et al. 2016

Journal of Structural Biology

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The anti-arthritic gold-containing drug Auranofin is lethal to the protozoan intestinal parasite Entamoeba histolytica, the causative agent of human amebiasis, in both culture and animal models of the disease. A putative mechanism of Auranofin action proposes that monovalent gold, Au(I), released from the drug, can bind to the redox-active dithiol group of thioredoxin reductase (TrxR). Au(I) binding in the active site is expected to prevent electron transfer to the downstream substrate thioredoxin (Trx), thus interfering with redox homeostasis in the parasite. To clarify the molecular mechanism of Auranofin action in more detail, we determined a series of atomic resolution x-ray structures for E. histolytica thioredoxin (EhTrx) and thioredoxin reductase (EhTrxR), the latter with and without Auranofin. Only the disulfide-bonded form of the active site dithiol (Cys140-Cys143) was invariably observed in crystals of EhTrxR in spite of the addition of reductants in various crystallization trials, and no gold was found associated with these cysteines. Non-catalytic Cys286 was identified as the only site of modification, but further mutagenesis studies using the C286Q mutant demonstrated that this site was not responsible for inhibition of EhTrxR by Auranofin. Interestingly, we obtained both of the catalytically-relevant conformations of this bacterial-like, low molecular weight TrxR in crystals without requiring an engineered disulfide linkage between Cys mutants of TrxR and Trx (as was originally done with E. coli TrxR and Trx). We note that the –CXXC– catalytic motif, even if reduced, would likely not provide space sufficient to bind Au(I) by both cysteines of the dithiol group.

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“…GSH发挥抗氧化作用既可以来自外源性添加也可以来自于内源性的蛋氨酸代谢. 饲粮中GSH可以在小肠部分吸收后合成 [43] , 并作为细胞抗氧化系统的主要成分, 直接清除自由基 [44,45] , 并且细胞可能失去将GSSG还原成GSH的能力, 从而导致GSSG在胞质溶胶中积累, 打破原有的氧化还原平衡状态.…”

Section: 谷胱甘肽是一种三肽(L-谷氨酰-l-半胱氨酰甘氨unclassified