Novel use of clinical drugs: Deubiquitinase inhibitor auranofin and disulfiram show synergistic anti-tumor effects in vitro and in vivo

Abstract

The deubiquitinases (DUBs) are emerging targets for cancer therapy. An increasing number of DUB inhibitors were discovered to be potential anti-tumor agents. We recently identified that auranofin (Aur), a gold-containing compound used clinically to treat rheumatoid arthritis, is an inhibitor of proteasome-associated DUBs. Besides its inherent anti-arthritis effect, Aur has been shown to exhibit a predominant anti-tumor property in various cancer phenotypes. Hence, we were prompted to enhance the anti-cancer capability of this promising drug. Disulfiram (DSF) is currently being used clinically for the treatment of alcoholism. Recent studies suggested that DSF could potentiate the effect of some other chemotherapeutic agents. In a recent study, we unraveled that Aur and DSF in combination potently induced apoptosis of hepatoma cells both in vitro and in vivo, and the synergistic cytotoxicity is associated with endoplasmic reticulum (ER) stress, loss of MMP, and caspase activation. Hence, we have identified a synergism model between two clinical drugs DUB inhibitor Aur and DSF in the induction of apoptosis as a potentially novel anticancer strategy for clinical use in the future.