Repurposing of auranofin: thioredoxin reductase remains a primary target of the drug.

Repurposing of auranofin: thioredoxin reductase remains a primary target of the drug. Biochimie. 2019 Apr 01;: Authors: Zhang X, Selvaraju K, Saei AA, D'Arcy P, Zubarev RA, Arnér ES, Linder S Abstract Auranofin is a gold (I)-containing compound used for the treatment of rheumatic arthritis. Auranofin has anticancer activity in animal models and is approved for clinical 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 inhibit proteasome activity at the level of the proteasome-associated deubiquitinases (DUBs) UCHL5 and USP14. We here set out to re-examine the molecular mechanism underlying auranofin cytotoxicity towards cultured cancer cells. The effects of auranofin on the proteasome was examined in cells and in vitro, effects on DUB activity was 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 induce oxidative stress response at IC50 doses. At 2 - 3-fold higher doses, auranofin inhibits proteasome processing in cells. At such supra-pharmacological concentrations USP14 activity was inhibited. Analysis of protein expression profiles in drug-exposed tumor cells showed that auranofi...
Source: Biochimie - Category: Biochemistry Authors: Tags: Biochimie Source Type: research