Pyrrolidine dithiocarbamate-zinc(II) and -copper(II) complexes induce apoptosis in tumor cells by inhibiting the proteasomal activity
Pyrrolidine dithiocarbamate-zinc(II) and -copper(II) complexes induce apoptosis in tumor cells by inhibiting the proteasomal activity
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DOI：
10.1016/j.taap.2008.03.009
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发表时间：
2008-08-15
影响因子：
3.8
通讯作者：
Dou, Q. Ping
中科院分区：
文献类型：
--
作者：
Milacic, Vesna;Chen, Di;Dou, Q. Ping
锌和铜是生物体中许多金属酶正确折叠、稳定和催化活性所必需的微量元素。然而，锌和铜的动态平衡失调在许多类型的癌症中都有报道。我们以前已经证明了铜配合物诱导培养的人类癌细胞的蛋白酶体抑制和凋亡。在目前的研究中，我们假设锌络合物也可以抑制蛋白酶体凝乳酶样活性，该活性负责随后的细胞凋亡诱导。我们首次发现氯化锌能够抑制纯化的20S蛋白酶体的胰凝乳蛋白酶样活性，其IC50值为13.8mU，低于氯化铜(IC505.3mU)。然后，我们比较了吡咯烷二硫代氨基甲酸酯(PYDT)-锌(II)络合物和PYDT-铜(II)络合物在不同的人类乳腺和前列腺癌细胞系中抑制细胞蛋白酶体活性、抑制增殖和诱导凋亡的效力。在抑制蛋白酶体和诱导细胞凋亡方面，锌络合物一直不如铜络合物有效。此外，锌和铜的络合物似乎使用略有不同的机制来杀死肿瘤细胞。锌络合物能够激活钙蛋白酶途径，但不能激活caspase-3依赖途径，而铜络合物能够诱导两种蛋白水解酶的激活。此外，这些吡啶脱氧核糖核酸金属络合物的效力取决于金属的性质，也取决于吡啶脱氧核苷与金属离子的比例，这可能会影响它们与肿瘤细胞中蛋白酶体相互作用和抑制的稳定性和有效性。(C)2008 Elsevier Inc.保留所有权利。
Zinc and copper are trace elements essential for proper folding, stabilization and catalytic activity of many metalloenzymes in living organisms. However, disturbed zinc and copper homeostasis is reported in many types of cancer. We have previously demonstrated that copper complexes induced proteasome inhibition and apoptosis in cultured human cancer cells. In the current study we hypothesized that zinc complexes could also inhibit the proteasomal chymotrypsin-like activity responsible for subsequent apoptosis induction. We first showed that zinc(II) chloride was able to inhibit the chymotrypsin-like activity of a purified 20S proteasome with an IC50 value of 13.8 mu M, which was less potent than copper(II) chloride (IC50 5.3 mu M). We then compared the potencies of a pyrrolidine dithiocarbamate (PyDT)-zinc(II) complex and a PyDT-copper(II) complex to inhibit cellular proteasomal activity, suppress proliferation and induce apoptosis in various human breast and prostate cancer cell lines. Consistently, zinc complex was less potent than copper complex in inhibiting the proteasome and inducing apoptosis. Additionally, zinc and copper complexes appear to use somewhat different mechanisms to kill tumor cells. Zinc complexes were able to activate calpain-, but not caspase-3-dependent pathway, while copper complexes were able to induce activation of both proteases. Furthermore, the potencies of these PyDT-metal complexes depend on the nature of metals and also on the ratio of PyDT to the metal ion within the complex, which probably affects their stability and availability for interacting with and inhibiting the proteasome in tumor cells. (c) 2008 Elsevier Inc. All rights reserved.