Thymoquinone induces apoptosis through activation of caspase-8 and mitochondrial events in p53-null myeloblastic leukemia HL-60 cells
Mohamed A. El-Mahdy
Department of Radiology, Ohio State University, Columbus, OH, USA
Search for more papers by this authorQianzheng Zhu
Department of Radiology, Ohio State University, Columbus, OH, USA
Search for more papers by this authorQi-En Wang
Department of Radiology, Ohio State University, Columbus, OH, USA
Search for more papers by this authorGulzar Wani
Department of Radiology, Ohio State University, Columbus, OH, USA
Search for more papers by this authorCorresponding Author
Altaf A. Wani
Department of Radiology, Ohio State University, Columbus, OH, USA
Biochemistry Program, Ohio State University, Columbus, OH, USA
James Cancer Hospital and Research Institute, Ohio State University, Columbus, OH, USA
Fax: +614-292-7237
Department of Radiology, The Ohio State University, 103 Wiseman Hall, 400 W. 12th Ave., Columbus, OH 43210, USASearch for more papers by this authorMohamed A. El-Mahdy
Department of Radiology, Ohio State University, Columbus, OH, USA
Search for more papers by this authorQianzheng Zhu
Department of Radiology, Ohio State University, Columbus, OH, USA
Search for more papers by this authorQi-En Wang
Department of Radiology, Ohio State University, Columbus, OH, USA
Search for more papers by this authorGulzar Wani
Department of Radiology, Ohio State University, Columbus, OH, USA
Search for more papers by this authorCorresponding Author
Altaf A. Wani
Department of Radiology, Ohio State University, Columbus, OH, USA
Biochemistry Program, Ohio State University, Columbus, OH, USA
James Cancer Hospital and Research Institute, Ohio State University, Columbus, OH, USA
Fax: +614-292-7237
Department of Radiology, The Ohio State University, 103 Wiseman Hall, 400 W. 12th Ave., Columbus, OH 43210, USASearch for more papers by this authorAbstract
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 antiproliferative 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. © 2005 Wiley-Liss, Inc.
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