Resistance to enzalutamide (androgen receptor [AR] antagonist) for castration-resistant prostate cancer (CRPC) therapy develops rapidly often by increasing AR activity. We discovered that multi-deubiquitinase (DUB) inhibitors such as betulinic acid (BA) and WP1130 can reduce expression of AR. DUBs protect multiple proteins from degradation by the ubiquitin-proteasome system. Therefore, combining multi-DUB inhibitors BA or WP1130 with enzalutamide may provide a novel strategy for CRPC by further decreasing AR expression and increasing apoptotic cell death.
We discovered a new chemotherapy strategy using an inhibitor of the common protein cyclophilin in combination with proteasome inhibitors. Our data in prostate, lung, melanoma, and hepatocellular cancer cells supports this strategy by amplifying proteotoxic stress, overwhelming pro-survival pathways, and forcing cancer cells towards apoptotic cell death without harming normal cells.