Anticancer activity of the antibiotic clioquinol
Anticancer activity of the antibiotic clioquinol
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DOI：
10.1158/0008-5472.can-04-3577
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发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Lind, SE
中科院分区：
文献类型：
--
作者：
Ding, WQ;Liu, BL;Lind, SE
氯碘羟喹是一种金属螯合剂，多年来一直被用作抗菌剂，最近被用作阿尔茨海默病的潜在治疗方法。因为它结合铜和锌，对酶超氧化物歧化酶-1（SOD 1）的活性至关重要的金属，这是抗癌药物开发的潜在靶点，我们研究了它对人类癌细胞的影响。氯碘羟喹治疗以浓度依赖性方式降低了8种不同人类癌细胞系的活力，IC 50值在低微摩尔范围内。生物化学分析显示氯碘羟喹通过需要半胱天冬酶活性的凋亡途径诱导癌细胞死亡。虽然氯碘羟喹在处理的细胞中诱导适度的SOD 1活性抑制，但已知的SOD 1抑制剂二乙基二硫代氨基甲酸酯的类似抑制作用不会导致细胞毒性。此外，铜，铁，或锌并没有拯救细胞从clquinol诱导的细胞毒性，但增强其杀伤，反对金属螯合作为其主要的作用机制。为了测试氯碘羟喹是否可以作为离子载体，使用荧光探针监测细胞内锌浓度。氯碘羟喹的加入导致细胞内锌水平升高，表明氯碘羟喹充当锌离子载体。在体内异种移植物小鼠模型中，氯碘羟喹在6周内抑制异种移植物的肿瘤生长，而不诱导可见的毒性。我们的研究结果表明氯碘羟喹在体外和体内都有抗癌作用。过渡金属离子载体可能是具有抗癌活性的金属螯合剂的一个亚类，值得进一步开发。
Clioquinol, a metal chelator, has been used for many years as an antimicrobial agent and more recently as a potential treatment for Alzheimer's disease. Because it binds copper and zinc, metals essential for the activity of the enzyme superoxide dismutase-1 (SOD1), a potential target for anticancer drug development, we investigated its effects on human cancer cells. Treatment with clioquinol reduced the viability of eight different human cancer cell lines in a concentration-dependent manner, with IC50 values in the low micromolar range. Biochemical analysis revealed that clioquinol induced cancer cell death through apoptotic pathways that require caspase activity. Although clioquinol induced modest inhibition of SOD1 activity in treated cells, comparable inhibition by a known SOD1 inhibitor, diethyldithiocarbamate, did not result in cytotoxicity. The addition of copper, iron, or zinc did not rescue cells from cliquinol-induced cytotoxicity but enhanced its killing, arguing against metal chelation as its major mechanism of action. To test if clioquinol might act as an ionophore, a fluorescent probe was used to monitor intracellular zinc concentrations. The addition of clioquinol resulted in elevated levels of intracellular zinc, indicating that clioquinol acts as a zinc ionophore. In an in vivo xenografts mouse model, clioquinol inhibited tumor growth of xenografts over a 6-week period, without inducing visible toxicity. Our results show that clioquinol has anticancer effects both in vitro and in vivo. Transition metal ionophores may be a subclass of metal chelators with anticancer activity deserving of further development.