Platinum resistant cancer cells conserve sensitivity to BH3 domains and obatoclax induced mitochondrial apoptosis
Platinum resistant cancer cells conserve sensitivity to BH3 domains and obatoclax induced mitochondrial apoptosis
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DOI：
10.1007/s10495-010-0561-1
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发表时间：
2011-03-01
期刊：
影响因子：
7.2
通讯作者：
Fennell, Dean A.
中科院分区：
文献类型：
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作者：
Crawford, Nyree;Chacko, Alex D.;Fennell, Dean A.
顺铂化疗耐药仍然是阻碍许多实体瘤有效治疗的主要障碍。BAX和BAK是线粒体凋亡途径的关键调节因子，然而，对于它们在顺铂耐药细胞中的调节机制知之甚少。顺铂在敏感细胞和耐药细胞中都会诱导DNA损伤，然而后者无法启动线粒体BAK的N末端暴露或线粒体SMAC的释放。这两种表型对外源性的源自BID、BIM、NOXA（靶向MCL - 1和A1）的BH3结构域肽诱导的线粒体通透性改变高度敏感，并且它们的促存活BCL2蛋白表达谱没有显著变化。Obatoclax是一种包括MCL - 1在内的促存活BCL - 2家族蛋白的小分子抑制剂，在一组因奥沙利铂耐药而筛选出的细胞系中，无论铂类耐药情况如何，它都会降低细胞活力。总之，铂类耐药的产生与BAX/BAK激活上游的线粒体死亡信号传导受阻有关。对BH3结构域诱导凋亡的敏感性的保守性可被诸如obatoclax等直接作用于线粒体和BCL - 2家族的药物所利用。
Resistance to cisplatin chemotherapy remains a major hurdle preventing effective treatment of many solid cancers. BAX and BAK are pivotal regulators of the mitochondrial apoptosis pathway, however little is known regarding their regulation in cisplatin resistant cells. Cisplatin induces DNA damage in both sensitive and resistant cells, however the latter exhibits a failure to initiate N-terminal exposure of mitochondrial BAK or mitochondrial SMAC release. Both phenotypes are highly sensitive to mitochondrial permeabilisation induced by exogenous BH3 domain peptides derived from BID, BIM, NOXA (which targets MCL-1 and A1), and there is no significant change in their prosurvival BCL2 protein expression profiles. Obatoclax, a small molecule inhibitor of pro-survival BCL-2 family proteins including MCL-1, decreases cell viability irrespective of platinum resistance status across a panel of cell lines selected for oxaliplatin resistance. In summary, selection for platinum resistance is associated with a block of mitochondrial death signalling upstream of BAX/BAK activation. Conservation of sensitivity to BH3 domain induced apoptosis can be exploited by agents such as obatoclax, which directly target the mitochondria and BCL-2 family.