Inhibition of prostate cancer cellular proteasome activity by a pyrrolidine dithiocarbamate-copper complex is associated with suppression of proliferation and induction of apoptosis
Inhibition of prostate cancer cellular proteasome activity by a pyrrolidine dithiocarbamate-copper complex is associated with suppression of proliferation and induction of apoptosis
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DOI：
10.2741/1749
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发表时间：
2005-09-01
影响因子：
3.1
通讯作者：
Dou, QP
中科院分区：
文献类型：
--
作者：
Chen, D;Peng, FY;Dou, QP
近期研究表明，铜可作为癌症治疗的一种新型选择性靶点。铜是肿瘤血管生成过程中必不可少的辅助因子，在许多类型的人类癌症中都发现了高水平的铜，包括前列腺癌、乳腺癌和脑癌。我们已经报道过，含铜有机化合物，如8 - 羟基喹啉 - 铜（II），是一类新型的蛋白酶体抑制剂和肿瘤细胞凋亡诱导剂（丹尼尔等人，《生物化学与药理学》，2004年；67卷：1139 - 1151页）。最近，我们发现当与铜络合时，已知的抗氧化剂吡咯烷二硫代氨基甲酸酯（PDTC）在人乳腺癌细胞中形成一种有效的蛋白酶体抑制剂，但在正常细胞中则不然（丹尼尔、陈等人，已投稿）。在当前的研究中，我们探讨PDTC - 铜复合物是否能在抑制人前列腺癌细胞的蛋白酶体活性并进而诱导细胞凋亡方面发挥类似的作用。我们使用四硫代钼酸盐（TM），一种目前正在临床试验中测试的强铜螯合剂，作为对照。我们在此报告，在与铜结合后，PDTC而非TM能够抑制蛋白酶体的类胰凝乳蛋白酶活性，抑制增殖，诱导细胞凋亡，并抑制培养的人前列腺癌细胞对放射性药物2 - [F - 18]氟 - 2 - 脱氧 - D - 葡萄糖的摄取。相比之下，单独的PDTC、TM或铜，或者TM - 铜混合物都没有这种作用。我们的研究表明，体内人前列腺癌中的高铜水平可被诸如PDTC之类的配体作为靶点，从而在前列腺肿瘤细胞而非正常细胞中特异性地形成一种活性蛋白酶体抑制剂和细胞凋亡诱导剂。
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-[F-18] 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.