Disulfiram (DSF), a member of the dithiocarbamate family capable of binding
copper and an inhibitor of
aldehyde dehydrogenase, is currently being used clinically for the treatment of
alcoholism. Recent studies have suggested that DSF may have antitumor and chemosensitizing activities, although the detailed molecular mechanisms remain unclear.
Copper has been shown to be essential for
tumor angiogenesis processes. Consistently, high serum and tissue levels of
copper have been found in many types of human
cancers, including breast, prostate, and brain, supporting the idea that
copper could be used as a potential
tumor-specific target. Here we report that the DSF-
copper complex potently inhibits the proteasomal activity in cultured
breast cancer MDA-MB-231 and MCF10DCIS.com cells, but not normal, immortalized MCF-10A cells, before induction of apoptotic
cancer cell death. Furthermore, MDA-MB-231 cells that contain
copper at concentrations similar to those found in patients, when treated with just DSF, undergo
proteasome inhibition and apoptosis. In addition, when administered to mice bearing MDA-MB-231
tumor xenografts, DSF significantly inhibited the
tumor growth (by 74%), associated with in vivo
proteasome inhibition (as measured by decreased levels of
tumor tissue
proteasome activity and accumulation of
ubiquitinated proteins and natural
proteasome substrates p27 and Bax) and apoptosis induction (as shown by
caspase activation and apoptotic nuclei formation). Our study shows that inhibition of the proteasomal activity can be achieved by targeting
tumor cellular
copper with the nontoxic compound DSF, resulting in selective apoptosis induction within
tumor cells.