The amaryllidaceae isocarbostyril narciclasine induces apoptosis by activation of the death receptor and/or mitochondrial pathways in cancer cells but not in normal fibroblasts
The amaryllidaceae isocarbostyril narciclasine induces apoptosis by activation of the death receptor and/or mitochondrial pathways in cancer cells but not in normal fibroblasts
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DOI：
10.1593/neo.07535
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发表时间：
2007-09-01
期刊：
影响因子：
4.8
通讯作者：
Kiss, Robert
中科院分区：
文献类型：
--
作者：
Dumont, Patrick;Ingrassia, Laurent;Kiss, Robert
我们的研究表明，石蒜科异喹诺酮那昔拉辛通过触发至少在人MCF-7乳腺癌和PC-3前列腺癌细胞中的死亡受体途径的起始半胱天冬酶（半胱天冬酶-8和半胱天冬酶-10）的激活，在人癌细胞中诱导显著的凋亡介导的细胞毒性作用，但在正常成纤维细胞中不诱导。在MCF-7和PC-3癌细胞中清楚地证明了Fas和死亡受体4（DR 4）死亡诱导信号复合物的形成。Caspase-8与Fas和DR 4受体相互作用。然而，在MCF-7细胞中，那昔拉辛诱导的下游凋亡途径与PC-3细胞中的那些途径不同，在PC-3细胞中，caspase-8在没有任何进一步释放线粒体促凋亡效应物的情况下直接激活效应物caspase-3，例如caspase-3。相比之下，在MCF-7细胞中，发现凋亡过程需要一个扩增步骤，该步骤是依赖于DNA的，具有Bid加工、细胞色素c的释放和半胱天冬酶-9活化。据推测，那西克拉新对癌细胞的高选择性可能至少部分地与死亡受体途径的激活有关。正常人成纤维细胞对那环拉西的敏感性降低约250倍，那环拉西不诱导这些细胞的凋亡，可能是由于缺乏死亡受体途径活化。
Our study has shown that the Amaryllidaceae isocarbostyril narciclasine induces marked apoptosis-mediated cytotoxic effects in human cancer cells but not in normal fibroblasts by triggering the activation of the initiator caspases of the death receptor pathway ( caspase-8 and caspase-10) at least in human MCF-7 breast and PC-3 prostate carcinoma cells. The formation of the Fas and death receptor 4 ( DR4) death-inducing signaling complex was clearly evidenced in MCF-7 and PC-3 cancer cells. Caspase-8 was found to interact with Fas and DR4 receptors on narciclasine treatment. However, narciclasine-induced downstream apoptotic pathways in MCF-7 cells diverged from those in PC-3 cells, where caspase-8 directly activated effector caspases such as caspase-3 in the absence of any further release of mitochondrial proapoptotic effectors. In contrast, in MCF-7 cells, the apoptotic process was found to require an amplification step that is mitochondria-dependent, with Bid processing, release of cytochrome c, and caspase-9 activation. It is postulated that the high selectivity of narciclasine to cancer cells might be linked, at least in part, to this activation of the death receptor pathway. Normal human fibroblasts appear approximately 250-fold less sensitive to narciclasine, which does not induce apoptosis in these cells probably due to the absence of death receptor pathway activation.