Inhibition of prostate cancer cellular proteasome activity by a pyrrolidine dithiocarbamate-copper complex is associated with suppression of proliferation and induction of apoptosis

Recent research suggests that copper could be used as a novel selective target for cancer therapies. Copper is a co-factor essential for tumor angiogenesis processes and high levels of copper have been found in many types of human cancers, including prostate, breast and brain. We have reported that organic copper-containing compounds, such as 8-hydroxyquinoline-copper(II), are a novel class of proteasome inhibitors and tumor cell apoptosis inducers (Daniel et al., Biochem Pharmacol. 2004;67:1139-51). Most recently, we have found that when complexed with copper, the known antioxidant pyrrolidine dithiocarbamate (PDTC) forms a potent proteasome inhibitor in human breast cancer, but not normal cells (Daniel, Chen, et al., submitted). In the current study, we investigate whether the PDTC-copper complex can play similar roles in inhibiting the proteasomal activity and consequently inducing apoptosis in human prostate cancer cells. We used tetrathiomolybdate (TM), a strong copper chelator currently being tested in clinical trials, as a control. We report here that after binding to copper, PDTC, but not TM, can inhibit the proteasomal chymotrypsin-like activity, suppress proliferation, induce apoptotic cell death, and inhibit uptake of radiopharmaceutical 2-[¹⁸F]Fluoro-2-deoxy-D- glucose in cultured human prostate cancer cells. In contrast, PDTC, TM or copper alone or a TM-copper mixture had no such effects. Our study suggests that high copper levels in human prostate cancer in vivo can be targeted by a ligand such as PDTC, resulting in formation of an active proteasome inhibitor and apoptosis inducer specifically in prostate tumor, but not normal cells.