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Int J Cancer. 2006 Mar 15;118(6):1577-80.

Inhibition of proteasome activity, nuclear factor-KappaB translocation and cell survival by the antialcoholism drug disulfiram.

Author information

1
Department of Medical Sciences, Division of Clinical Pharmacology, University Hospital, Uppsala University, 751 85 Uppsala, Sweden. Henrik.Lovborg@medsci.uu.se

Abstract

The proteasome pathway is an important target for anticancer drug development. Here, we identify the antialcoholism drug disulfiram and its analogue pyrrolidine dithiocarbamate (PDTC) as inhibitors of the 26S proteasome activity in a cell-based screening assay. As expected for proteasome inhibitors, these compounds also inhibited TNF-alpha-induced nuclear factor-KappaB (NF-KappaB) translocation and were cytotoxic. Disulfiram was more cytotoxic against chronic lymphocytic leukemia cells compared to peripheral blood mononuclear cells (PBMC) at clinically achievable concentrations. Proteasome and NF-KappaB inhibition were achieved with a potency in the same range as that of the clinically used proteasome inhibitor bortezomib. Disulfiram was also able to induce accumulation of p27(Kip1) and to prolong the half-life of c-Myc, both targets for proteasome-dependent degradation. It is concluded that the previously observed antitumoral and NF-KappaB inhibiting activity of disulfiram and PDTC could be attributed to their inhibition of the 26S proteasome.

PMID:
16206267
DOI:
10.1002/ijc.21534
[Indexed for MEDLINE]
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