The histone deacetylase inhibitor MS-275 induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia cells
The histone deacetylase inhibitor MS-275 induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia cells
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DOI：
10.1038/sj.leu.2403388
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发表时间：
2004-07-01
期刊：
影响因子：
11.4
通讯作者：
Grever, MR
中科院分区：
文献类型：
--
作者：
Lucas, DM;Davis, ME;Grever, MR
MS-275是一种组蛋白去乙酰化酶（HDAC）抑制剂，据报道，它通过在增殖的造血细胞系中产生活性氧（ROS）来介导其细胞毒性作用。我们检测了MS-275对来自患者的非增殖性慢性淋巴细胞白血病（CLL）细胞的疗效。在这些细胞中，MS-275显示出比正常单核细胞低一个对数的体外LC50。MS-275处理后，组蛋白H3和H4乙酰化增加，HDAC酶活性降低。激活caspase -8、-9和-3，裂解caspase底物PARP和BID。此外，MS-275孵育后，FLIP抑制蛋白（FLIP）下调。MS-275处理15h后产生可检测到的ROS，被caspase抑制剂Z-VAD-fmk阻断。Bcl-2蛋白过表达对ms -275诱导的细胞凋亡有保护作用。这些数据表明MS-275是一种治疗CLL的有希望的疗法，但与之前的报道相反，ROS的产生并不先于细胞凋亡。与许多其他治疗靶点类似，ms -275介导的细胞凋亡通过Bcl-2的过度表达而减少，这证明了将HDAC抑制剂与Bcl-2拮抗剂联合使用的策略是合理的。
MS-275 is a histone deacetylase ( HDAC) inhibitor that has been reported to mediate its cytotoxic effect through generation of reactive oxygen species (ROS) in proliferating hematopoietic cell lines. We examined efficacy of MS-275 in nonproliferating chronic lymphocytic leukemia (CLL) cells from patients. In these cells, MS-275 demonstrated an in vitro LC50 that was one log lower than for normal mononuclear cells. Following MS-275 treatment, histones H3 and H4 showed increased acetylation and HDAC enzymatic activity was reduced. Caspase-8, -9, and -3 were activated, and caspase substrates PARP and BID were cleaved. Additionally, FLICE-inhibitory protein ( FLIP) was downmodulated following MS-275 incubation. MS-275 treatment caused detectable ROS generation after 15 h of incubation, which was blocked by the caspase inhibitor Z-VAD-fmk. Overexpression of Bcl-2 protein protected against MS-275-induced apoptosis. These data demonstrate that MS-275 is a promising therapy for the treatment of CLL, but that in contrast to previous reports, ROS generation does not precede commitment to apoptosis. Similar to many other therapeutic targets, MS-275-mediated apoptosis is reduced by overexpression of Bcl-2, justifying strategies to combine HDAC inhibitors with Bcl-2 antagonists.