A valuable strategy to develop new therapeutic options for a variety of diseases has been the identification of new targets and applications for already approved drugs, the so-called
drug repositioning. Recurrent
ovarian cancer is a nearly incurable
malignancy for which new and effective treatments are urgently needed. The alcohol-deterring
drug disulfiram has been shown to cause preferential cell death in a variety of
cancer cells. In this study, it is shown that
disulfiram mediates effective cell death in
ovarian cancer cells by promoting a pro-oxidative intracellular environment in a
copper-dependent mechanism. Within few hours of application,
disulfiram caused irreversible cell damage associated with pronounced induction of the inducible
heat shock proteins HSP70, HSP40, and HSP32. The
small heat shock protein HSP27 was found to be covalently dimerized via oxidized
disulfide bonds and precipitated in para-
nuclear protein aggregates. Simultaneous inhibition of the cellular
thioredoxin system by
auranofin further enhanced the cytotoxic effect of
disulfiram. These data indeed indicate that the combination of two approved drugs, the anti-alcoholic
disulfiram and the anti-rheumatic
auranofin, may be of interest for the treatment of recurrent and genotoxic
drug-resistant
ovarian cancer by inducing a proteotoxic cell death mechanism.