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

Abstract

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.

Pyrrolidine dithiocarbamate-zinc(II) and -copper(II) complexes induce apoptosis in tumor cells by inhibiting the proteasomal activity

“…Inhibition of the proteasomal activity leads to the accumulation of IκB-α, resulting in NF-κB inactivation. We have previously reported an ubiquitinated form of IκB-α protein with molecular weight of ~56 kDa (Chen et al, 2005a). A similar p56 band appeared after the treatment with 10 and 20 μmol/L PyDT-zinc and 1,10 and 20 μmol/L PyDT-copper mixture (Fig.…”

“…However, when combined with either zinc(II) or copper(II) chloride, PyDT was shown to inhibit the ubiquitin-proteasome pathway (Kim et al, 2004;Daniel et al, 2005;Chen et al, 2005a). We have previously shown that PyDT-copper inhibits proliferation and induces apoptosis in cultured breast and prostate cancer cells by inhibiting proteasomal chymotrypsin-like activity (Daniel et al, 2005;Chen et al, 2005a). Based on that and similar location of zinc and copper in the periodic table, we hypothesized that the PyDT-zinc complex could have similar effect on the proteasome.…”

“…One of the dithiocarbamates, pyrrolidine dithiocarbamate (PyDT), is a synthetic analog that has been reported to inhibit nuclear factor kappa B (NFκB) activation (Parodi et al, 2005;Schreck et al, 1992). However, when combined with either zinc(II) or copper(II) chloride, PyDT was shown to inhibit the ubiquitin-proteasome pathway (Kim et al, 2004;Daniel et al, 2005;Chen et al, 2005a). We have previously shown that PyDT-copper inhibits proliferation and induces apoptosis in cultured breast and prostate cancer cells by inhibiting proteasomal chymotrypsin-like activity (Daniel et al, 2005;Chen et al, 2005a).…”

Oral administration of Pyrrolidine Dithiocarbamate (PDTC) inhibits VEGF expression, tumor angiogenesis, and growth of breast cancer in female mice

“…14,15 Of these, PDTC is the most potent NFκB inhibitor. 16 PDTC has been shown to inhibit NFκB activation for suppressing tumor growth in colorectal cancer, 17 and for inducing pro-apoptotic and anti-proliferative effects in prostate cancer, 18 ovarian carcinoma cells, 19 breast cancer cells, 20 T-cell leukemia, 21 lymphoma, 22 gastric cancer cells 23 and renal cell carcinoma. 24 The expression of genes, such as vascular endothelial growth factor (VEGF), is also stimulated by NFκB, which is involved in angiogenesis.…”

Copper ions regulate cytotoxicity of disulfiram to myeloid leukemia cells

“…The tumor suppressive effects of DSF often depend on passive cellular uptake of this drug in complexes with copper. Copper ions were shown to be involved in regulation of dithiocarbamate-induced apoptosis of thymocytes, prostate cancer cells, astrocytes and melanoma cells (12,13,(15)(16)(17)(18). Recently, the copper-mediated inhibition of histone acetyltransferase activity and induction of apoptosis in pyrrolidine dithiocarbamate-treated leukemic cells have also been reported (19).…”