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

✍ Scribed by Henrik Lövborg; Fredrik Öberg; Linda Rickardson; Joachim Gullbo; Peter Nygren; Rolf Larsson

Book ID: 102275613
Publisher: John Wiley and Sons
Year: 2005
Tongue: French
Weight: 283 KB
Volume: 118
Category: Article
ISSN: 0020-7136
DOI: 10.1002/ijc.21534

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✦ Synopsis

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-a-induced nuclear factor-KB (NF-KB) 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-KB 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-KB inhibiting activity of disulfiram and PDTC could be attributed to their inhibition of the 26S proteasome.

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