The association of statins and taxanes: an efficient combination trigger of cancer cell apoptosis.
The association of statins and taxanes: an efficient combination trigger of cancer cell apoptosis.
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DOI：
10.1038/bjc.2012.6
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发表时间：
2012-02-14
影响因子：
8.8
通讯作者：
Le Jossic-Corcos C
中科院分区：
文献类型：
--
作者：
Follet J;Corcos L;Baffet G;Ezan F;Morel F;Simon B;Le Jossic-Corcos C
联合使用现有的药物可以杀死癌细胞。他汀类药物是主要的抗高胆固醇血症药物，其也引发许多癌细胞类型的凋亡，而多西他赛是一种有效的微管稳定剂。在这里，我们研究了洛伐他汀和多西他赛在癌细胞中的联合作用。HGT-1胃癌细胞的全转录组芯片显示，洛伐他汀强烈抑制参与细胞分裂的基因的表达，而多西他赛的转录影响很小。这两种药物都引发了细胞凋亡，它们的组合超过了累加。洛伐他汀单独或与多西他赛联合使用可诱导细胞周期抑制剂p21显著升高，同时极光激酶A和B、细胞周期蛋白B1和D1蛋白减少。药物处理诱导蛋白酶原-3的蛋白水解裂解，抗凋亡Mcl-1蛋白、聚ADP-核糖聚合酶和Bax的下降。引人注目的是，过表达MDR-1基因的紫杉醇耐药HGT-1细胞衍生物对洛伐他汀比紫杉醇敏感细胞更敏感。这些结果表明，联合洛伐他汀和多西他赛，或单独洛伐他汀，显示出作为合理的抗癌策略的前景，无论是作为一种直接的治疗方法或获得性P-糖蛋白依赖性耐药。
Cancer cell killing might be achieved by the combined use of available drugs. Statins are major anti-hypercholesterolemia drugs, which also trigger apoptosis of many cancer cell types, while docetaxel is a potent microtubule-stabilising agent. Here, we looked at the combined effects of lovastatin and docetaxel in cancer cells. Whole transcriptome microarrays in HGT-1 gastric cancer cells demonstrated that lovastatin strongly suppressed expression of genes involved in cell division, while docetaxel had very little transcriptional effects. Both drugs triggered apoptosis, and their combination was more than additive. A marked rise in the cell-cycle inhibitor p21, together with reduction of aurora kinases A and B, cyclins B1 and D1 proteins was induced by lovastatin alone or in combination with docetaxel. The drug treatments induced the proteolytic cleavage of procaspase-3, a drop of the anti-apoptotic Mcl-1 protein, Poly-ADP-Ribose Polymerase and Bax. Strikingly, docetaxel-resistant HGT-1 cell derivatives overexpressing the MDR-1 gene were much more sensitive to lovastatin than docetaxel-sensitive cells. These results suggest that the association of lovastatin and docetaxel, or lovastatin alone, shows promise as plausible anticancer strategies, either as a direct therapeutic approach or following acquired P-glycoprotein-dependent resistance.