Thymoquinone induces apoptosis through activation of caspase-8 and mitochondrial events in p53-null myeloblastic leukemia HL-60 cells
Thymoquinone induces apoptosis through activation of caspase-8 and mitochondrial events in p53-null myeloblastic leukemia HL-60 cells
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DOI：
10.1002/ijc.21205
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发表时间：
2005-11-10
影响因子：
6.4
通讯作者：
Wani, AA
中科院分区：
文献类型：
--
作者：
El-Mahdy, MA;Zhu, QZ;Wani, AA
百里醌（Thymoquinone，TQ）是从传统药用植物黑种草（Nigella sativa Linn）中分离得到的主要生物活性成分，是一种潜在的化学预防和化学治疗化合物。尽管TQ具有良好的抗肿瘤活性，但其药理作用的分子机制尚不清楚。在此，我们报告TQ具有抗增殖作用，诱导凋亡，破坏线粒体膜电位和触发激活半胱天冬酶8，9和3在髓性白血病HL-60细胞。TQ诱导的细胞凋亡可被caspase-3特异性抑制剂z-VAD-FMK、caspase-8特异性抑制剂z-DEVD-FMK和caspase-8特异性抑制剂z-IETD-FMK抑制。Caspase-8抑制剂可阻断CQ诱导的caspase-3活化、PARP裂解和细胞色素c从线粒体释放到细胞质中。此外，TQ处理HL-60细胞引起Bax/Bcl-2比值的显着增加，由于上调Bax和下调Bcl-2蛋白。这些结果表明，TQ诱导的细胞凋亡与caspase 8，9和3的激活有关，caspase-8作为上游激活剂。在TQ诱导的细胞凋亡过程中，活化的caspase-8启动细胞色素c的释放。总的来说，这些结果提供了一个潜在的机制，在p53-null HL-60癌细胞中的TQ诱导的凋亡。(c)2005 Wiley-Liss，Inc.
Thymoquinone (TQ), the major biologically active component isolated from a traditional medicinal herb, Nigella sativa Linn, is a potential chemopreventive and chemotherapeutic compound. Despite the promising antineoplastic activities of TQ, the molecular mechanism of its pharmacologic effects is poorly understood. Here, we report that TQ exhibits anti proliferative effect, induces apoptosis, disrupts mitochondrial membrane potential and triggers the activation of caspases 8, 9 and 3 in myeloblastic leukemia HL-60 cells. The apoptosis induced by TQ was inhibited by a general caspase inhibitor, z-VAD-FMK; a caspase-3-specific inhibitor, z-DEVD-FMK; as well as a caspase-8-specific inhibitor, z-IETD-FMK. Moreover, the caspase-8 inhibitor blocked the TQ-induced activation of caspase-3, PARP cleavage and the release of cytochrome c from mitochondria into the cytoplasm. In addition, TQ treatment of HL-60 cells caused a marked increase in Bax/Bcl2 ratios due to upregulation of Bax and downregulation of Bcl2 proteins. These results indicate that TQ-induced apoptosis is associated with the activation of caspases 8, 9 and 3, with caspase-8 acting as an upstream activator. Activated caspase-8 initiates the release of cytochrome c during TQ-induced apoptosis. Overall, these results offer a potential mechanism for TQ-induced apoptosis in p53-null HL-60 cancer cells. (c) 2005 Wiley-Liss, Inc.