Ding Wei-Qun, Liu Bolin, Vaught Joshua L, Palmiter Richard D, Lind Stuart E
University of Oklahoma Health Sciences Center, 975 Northeast 10th Street, BRC 409, Oklahoma City, OK 73104, USA.
Mol Cancer Ther. 2006 Jul;5(7):1864-72. doi: 10.1158/1535-7163.MCT-06-0067.
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-kappaB 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.
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），最近发现其在口服给药所能达到的浓度下，对人类癌细胞系具有细胞毒性活性。开展本研究的目的是确定氯碘羟喹是否能够增强两种药物——阿霉素和二十二碳六烯酸（DHA）的抗肿瘤作用，据信这两种药物部分是通过生成反应性氧化物种来发挥作用的。在低微摩尔浓度下，氯碘羟喹对细胞活力影响很小，也不能增强阿霉素的细胞毒性。氯碘羟喹显著增强了DHA的细胞毒性作用，等效线图分析表明这种相互作用具有协同性。氯碘羟喹与DHA在降低核因子-κB活性和诱导细胞凋亡方面表现出协同相互作用，并且联合用药降低了包括Akt、p65和Bcl-2在内的几种促进细胞存活分子的水平。有趣的是，氯碘羟喹本身既不诱导脂质过氧化，也不会增加添加DHA所导致的过氧化反应。然而，当用抗氧化剂维生素E对细胞进行预处理时，氯碘羟喹和DHA的协同作用被阻断，这表明脂质过氧化对它们的作用至关重要。这些发现揭示了一种新型的抗肿瘤药物组合，该组合协同靶向主要的细胞存活信号通路。
