Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells
Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells
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DOI：
10.1158/1535-7163.mct-06-0067
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发表时间：
2006-07-01
影响因子：
5.7
通讯作者：
Lind, Stuart E.
中科院分区：
文献类型：
--
作者：
Ding, Wei-Qun;Liu, Bolin;Lind, Stuart E.
氯碘羟喹是一种具有抗菌特性的8-羟基喹啉衍生物（5-氯-7-碘-8-羟基喹啉），最近发现在口服给药达到的浓度下对人癌细胞系具有细胞毒性活性。这项研究的目的是确定氯碘羟喹是否可以增强两种药物多柔比星和二十二碳六烯酸（DHA）的抗肿瘤作用，据信这两种药物部分通过生成反应物氧化剂起作用。在低微摩尔浓度下，氯碘羟喹对细胞活力几乎没有影响，并且不增强多柔比星的细胞毒性。氯碘羟喹显着增强DHA的细胞毒性作用，一种相互作用，被证明是协同作用的等效线分析。氯碘羟喹与DHA在降低核因子-κ B活性和诱导细胞凋亡方面表现出协同作用，并且该组合降低了促进细胞存活的几种分子的水平，包括Akt、p65和Bcl-2。有趣的是，氯碘羟喹本身既不诱导脂质过氧化，也不增加添加DHA所带来的过氧化。然而，当细胞用抗氧化剂维生素E预处理时，氯碘羟喹和DHA的协同作用被阻断，表明脂质过氧化对其作用的重要作用。这些发现揭示了一种新的抗肿瘤药物组合，协同靶向主要的细胞存活信号通路。
Clioquinol, an 8-hydroxyquinoline derivative (5-chloro-7-iodo-8-hydroxyquinoline) with antimicrobial properties, has recently been found to have cytotoxic activity towards human cancer cell lines at concentrations achieved by oral administration. This study was initiated to determine whether clioquinol could potentiate the antitumor effects of two drugs, doxorubicin and docosahexaenoic acid (DHA), believed to act in part via the generation of reactant oxidant species. At low micromolar concentrations, clioquinol had little effect upon cell viability and did not potentiate doxorubicin's cytotoxicity. Clioquinol significantly enhanced DHA's cytotoxic effects, an interaction that was shown to be synergistic by isobolographic analysis. Clioquinol exhibited a synergistic interaction with DHA in reducing nuclear factor-kappa B activity and inducing apoptosis, and the combination reduced the level of several molecules that promote cell survival, including Akt, p65, and Bcl-2. Interestingly, clioquinol neither induced lipid peroxidation itself nor increased peroxidation brought about by the addition of DHA. However, when cells were pretreated with antioxidant vitamin E, the synergism of clioquinol and DHA was blocked, indicating the essential role of lipid peroxidation for their action. These findings reveal a novel antitumor drug combination that synergistically targets major cell survival signaling pathways.