Copper-Dependent Cytotoxicity of 8-Hydroxyquinoline Derivatives Correlates with Their Hydrophobicity and Does Not Require Caspase Activation
Copper-Dependent Cytotoxicity of 8-Hydroxyquinoline Derivatives Correlates with Their Hydrophobicity and Does Not Require Caspase Activation
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DOI：
10.1021/jm301053a
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发表时间：
2012-12-13
影响因子：
7.3
通讯作者：
Marchio, Luciano
中科院分区：
文献类型：
--
作者：
Tardito, Saverio;Barilli, Amelia;Marchio, Luciano
本文报道了一系列8-羟基喹啉衍生物（8-HQ）的构效关系，重点研究了5-Cl-7-I-8-HQ（氯碘喹啉，CQ）铜配合物（Cu（CQ））的细胞毒活性。8-单独使用HQ会导致人肿瘤HeLa和PC 3细胞活力的剂量依赖性丧失，但同时使用铜会增加配体效应，导致两种细胞系中均发生广泛的细胞死亡。细胞毒性剂量的铜（CQ）促进细胞内铜的积累和大量的内质网空泡化之前的非凋亡（近凋亡）细胞死亡。Cu（CQ）的细胞毒性作用在正常人内皮细胞（HUVEC）中以两倍于肿瘤细胞中有效浓度的浓度再现，指出Cu（CQ）的潜在治疗窗口。最后，结果表明，铜（CQ）诱导的paraptotic细胞死亡不需要也不涉及半胱天冬酶，目前的临床评估氯碘羟喹作为一种抗肿瘤剂的指示。
This study reports the structure-activity relationship of a series of 8-hydroxoquinoline derivatives (8-HQs) and focuses on the cytotoxic activity of 5-Cl-7-I-8-HQ (clioquinol, CQ) copper complex (Cu(CQ)). 8-HQs alone cause a dose-dependent loss of viability of the human tumor HeLa and PC3 cells, but the coadministration of copper increases the ligands effects, with extensive cell death occurring in both cell lines. Cytotoxic doses of Cu(CQ) promote intracellular copper accumulation and massive endoplasmic reticulum vacuolization that precede a nonapoptotic (paraptotic) cell death. The cytotoxic effect of Cu(CQ) is reproduced in normal human endothelial cells (HUVEC) at concentrations double those effective in tumor cells, pointing to a potential therapeutic window for Cu(CQ). Finally, the results show that the paraptotic cell death induced by Cu(CQ) does not require nor involve caspases, giving an indication for the current clinical assessment of clioquinol as an antineoplastic agent.