SMAC mimetics sensitize nonsteroidal anti-inflammatory drug-induced apoptosis by promoting caspase-3-mediated cytochrome c release
SMAC mimetics sensitize nonsteroidal anti-inflammatory drug-induced apoptosis by promoting caspase-3-mediated cytochrome c release
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DOI：
10.1158/0008-5472.can-07-5242
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发表时间：
2008-01-01
期刊：
影响因子：
11.2
通讯作者：
Zhang, Lin
中科院分区：
文献类型：
--
作者：
Bank, Alexander;Wang, Peng;Zhang, Lin
非甾体抗炎药（NSAID）可有效抑制结直肠肿瘤的形成。然而，NSAIDs的潜在作用机制仍不清楚。NSAIDs的作用是不完全的，并且对NSAIDs的耐药性经常发展。越来越多的证据表明，NSAIDS的化学预防活性是通过诱导细胞凋亡介导的。我们以前的研究表明，第二种来源于caspase的激活剂（SMAC）/Diablo，一种线粒体促凋亡蛋白，在NSAID诱导的结肠癌细胞凋亡中起着至关重要的作用。在这项研究中，我们发现，SMAC通过反馈放大机制介导NSAID诱导的细胞凋亡，涉及与凋亡蛋白抑制剂的相互作用，激活caspase-3，并诱导细胞色素c的胞浆释放。纳摩尔浓度的小分子SMAC模拟物通过促进半胱天冬酶-3活化和细胞色素c释放，显著使结肠癌细胞对NSAID诱导的凋亡敏感。此外，SMAC模拟物通过恢复半胱天冬酶-3活化和细胞色素c释放来克服NSAID缺陷或SMAC缺陷结肠癌细胞中的NSAID抗性。总之，这些结果表明，SMAC是有用的目标，为发展更有效的化学预防策略和代理。
Nonsteroidal anti-inflammatory drugs (NSAID) are effective in suppressing the formation of colorectal tumors. However, the mechanisms underlying the antineoplastic effects of NSAIDs remain unclear. The effects of NSAIDs are incomplete, and resistance to NSAIDs is often developed. Growing evidence has indicated that the chemopreventive activity of NSAIDS is mediated by induction of apoptosis. Our previous studies showed that second mitochondria-derived activator of caspase (SMAC)/Diablo, a mitochondrial apoptogenic protein, plays an essential role in NSAID-induced apoptosis in colon cancer cells. In this study, we found that SMAC mediates NSAID-induced apoptosis through a feedback amplification mechanism involving interactions with inhibitor of apoptosis proteins, activation of caspase-3, and induction of cytosolic release of cytochrome c. Small-molecule SMAC mimetics at nanomolar concentrations significantly sensitize colon cancer cells to NSAID-induced apoptosis by promoting caspase-3 activation and cytochrome c release. Furthermore, SMAC mimetics overcome NSAID resistance in Bax-deficient or SMAC-deficient colon cancer cells by restoring caspase-3 activation and cytochrome c release. Together, these results suggest that SMAC is useful as a target for the development of more effective chemopreventive strategies and agents.