Synchrotron X-ray imaging reveals a correlation of tumor copper speciation with Clioquinol's anticancer activity.
Synchrotron X-ray imaging reveals a correlation of tumor copper speciation with Clioquinol's anticancer activity.
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DOI：
10.1002/jcb.22231
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发表时间：
2009-09-01
影响因子：
4
通讯作者：
Dou, Q. Ping
中科院分区：
文献类型：
--
作者：
Barrea, Raul A.;Chen, Di;Irving, Thomas C.;Dou, Q. Ping
肿瘤的发展和转移依赖于血管生成，这需要某些生长因子、蛋白酶和微量元素铜（Cu）。最近的研究表明，铜可用作癌症治疗的新靶点。氯碘羟喹（CQ）是一种能够与铜或锌（Zn）形成稳定络合物的抗生素，已在人类癌细胞和异种移植物中显示出蛋白酶体抑制活性、雄激素受体抑制活性、促凋亡活性和抗肿瘤活性。CQ与细胞内Cu的相互作用、Cu/Zn比值的改变以及CQ在体内的抗肿瘤作用的机制尚未完全阐明。我们在这里报告，铜积累在肿瘤组织和铜/锌平衡在肿瘤中，但不是正常的，组织与CQ治疗后的变化显着。Cu形态分析表明，Cu（I）的物种是在正常和肿瘤组织中占主导地位，铜（II）含量显着增加，而不是正常组织CQ治疗后，在肿瘤。我们的研究结果表明，CQ可以在体内与细胞Cu相互作用，失调Cu/Zn平衡，并能够在肿瘤组织中将Cu（I）转化为Cu（II）。Cu（I）向Cu（II）的这种转化可能与CQ诱导的蛋白酶体抑制和人前列腺肿瘤异种移植物中的生长抑制有关。
Tumor development and metastasis depend on angiogenesis that requires certain growth factors, proteases and the trace element copper (Cu). Recent studies suggest that Cu could be used as a novel target for cancer therapies. Clioquinol (CQ), an antibiotic that is able to form stable complexes with Cu or zinc (Zn), has shown proteasome-inhibitory activity, androgen receptor-suppressing, apoptosis-inducing and antitumor activities in human cancer cells and xenografts. The mechanisms underlying the interaction of CQ with cellular Cu, the alteration of the Cu/Zn ratio and the antitumor role of CQ in vivo have not been fully elucidated. We report here that Cu accumulates in tumor tissue and that the Cu/Zn balances in tumor, but not normal, tissue change significantly after the treatment with CQ. Cu speciation analysis showed that the Cu(I) species is predominant in both normal and tumor tissues and that Cu(II) content was significantly increased in tumor, but not normal tissue after CQ treatment. Our findings indicate that CQ can interact with cellular Cu in vivo, dysregulates the Cu/Zn balance and is able to convert Cu(I) to Cu(II) in tumor tissue. This conversion of Cu(I) to Cu(II) may be associated with CQ-induced proteasome inhibition and growth suppression in the human prostate tumor xenografts.
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