The Ca2+ channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells
The Ca2+ channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells
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DOI：
10.1007/s10495-010-0454-3
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发表时间：
2010-05-01
期刊：
影响因子：
7.2
通讯作者：
Hoskin, David W.
中科院分区：
文献类型：
--
作者：
Conrad, David M.;Furlong, Suzanne J.;Hoskin, David W.
Flunarizine 是一种 Ca2+ 通道阻滞剂，可以具有细胞保护性或细胞毒性，具体取决于所检查的细胞类型。我们在此表明，氟桂利嗪对 Jurkat T 白血病细胞以及其他血液恶性肿瘤具有细胞毒性，但对乳腺癌或结肠癌细胞没有细胞毒性。用氟桂利嗪处理 Jurkat 细胞会导致 caspase-3 激活、聚 (ADP-核糖) 聚合酶裂解和 DNA 片段阶梯化，所有这些都是细胞凋亡的标志。氟桂利嗪诱导的 DNA 断裂被 caspase-3 抑制剂 z-DEVD-fmk、caspase-8/caspase-10 抑制剂 z-IETD-fmk 和 caspase-10 抑制剂 z-AEVD-fmk 抑制，但在 caspase-8 缺陷的 Jurkat 细胞中并未减少，表明 caspase-10 参与了 caspase-3 激活的上游。有趣的是，FADD 招募到死亡受体并不参与，因为氟桂利嗪导致 FADD 缺陷的 Jurkat 细胞中 DNA 断裂。氟桂利嗪处理 Jurkat 细胞还导致活性氧的产生、线粒体跨膜电位的耗散、线粒体中细胞色素 c 的释放以及 caspase-9 的激活，尽管这些事件都不是诱导细胞凋亡所必需的。总的来说，这些发现表明氟桂利嗪通过不依赖于 FADD 的 caspase-10 激活来触发 Jurkat 细胞凋亡。氟桂利嗪作为治疗血液恶性肿瘤的潜在抗癌药物值得进一步研究。
Flunarizine is a Ca2+ channel blocker that can be either cytoprotective or cytotoxic, depending on the cell type that is being examined. We show here that flunarizine was cytotoxic for Jurkat T-leukemia cells, as well as for other hematological maligancies, but not for breast or colon carcinoma cells. Treatment of Jurkat cells with flunarizine resulted in caspase-3 activation, poly (ADP-ribose) polymerase cleavage, and laddering of DNA fragments, all of which are hallmarks of apoptosis. Flunarizine-induced DNA fragmentation was inhibited by the caspase-3 inhibitor z-DEVD-fmk, the caspase-8/caspase-10 inhibitor z-IETD-fmk, and the caspase-10 inhibitor z-AEVD-fmk, but was not reduced in caspase-8-deficient Jurkat cells, indicating the involvement of caspase-10 upstream of caspase-3 activation. Interestingly, FADD recruitment to a death receptor was not involved since flunarizine caused DNA fragmentation in FADD-deficient Jurkat cells. Flunarizine treatment of Jurkat cells also resulted in reactive oxygen species production, dissipation of mitochondrial transmembrane potential, release of cytochrome c from mitochondria, and caspase-9 activation, although none of these events were necessary for apoptosis induction. Collectively, these findings indicate that flunarizine triggers apoptosis in Jurkat cells via FADD-independent activation of caspase-10. Flunarizine warrants further investigation as a potential anti-cancer agent for the treatment of hematological malignancies.