Disulfiram, and Disulfiram Derivatives as Novel Potential Anticancer Drugs Targeting the Ubiquitin Proteasome System in Both Preclinical and Clinical Studies

F.      R. Kona; D.      Buac; A.      M. Burger

Abstract

Disulfiram is a FDA approved drug for the treatment of alcoholism and has been available for clinical use for over five decades. Despite data from the 1970s and 80s, which showed that disulfiram and analogs are able to enhance the activity of anticancer cytotoxic drugs and might be useful as chemopreventative agents, the underlying molecular mechanisms remained unknown until recently. Large scale screening efforts for agents that can inhibit the proteasome and be used as novel anticancer drugs revealed that disulfiram has proteasome inhibitory activity. Moreover, disulfiram was also found to have specific activity against zinc fingers and RING-finger ubiquitin E3 ligases that play an important role in cancer development. Here we review the preclinical and clinical studies exploring disulfiram as an anticancer agent, as well as research programs that focus on the development of disulfiram derivatives as inhibitors of the ubiquitinproteasome system.

Keywords: Disulfiram, proteasome, ubiquitin E3 ligases, zinc ejection, zinc, copper, anticancer activity, clinical trials