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Inhibition of proteasome activity, nuclear factor‐KB translocation and cell survival by the antialcoholism drug disulfiram
Author(s) -
Lövborg Henrik,
Öberg Fredrik,
Rickardson Linda,
Gullbo Joachim,
Nygren Peter,
Larsson Rolf
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21534
Subject(s) - disulfiram , proteasome , bortezomib , proteasome inhibitor , pharmacology , lactacystin , aldehyde dehydrogenase , pyrrolidine dithiocarbamate , cytotoxic t cell , tumor necrosis factor alpha , chemistry , medicine , apoptosis , immunology , nf κb , biochemistry , in vitro , enzyme , multiple myeloma
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‐α‐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. © 2005 Wiley‐Liss, Inc.