Tliptolide induces caspase-dependent cell death mediated via the mitochondfial pathway in leukemic cells
Tliptolide induces caspase-dependent cell death mediated via the mitochondfial pathway in leukemic cells
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DOI：
10.1182/blood-2005-09-3898
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发表时间：
2006-07-15
期刊：
影响因子：
20.3
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
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作者：
Carter, Bing Z.;Mak, Duncan H.;Andreeff, Michael
雷公藤内酯醇是从中药雷公藤中分离得到的一种二萜类化合物，对多种实体瘤具有抗肿瘤活性。在这里，我们研究了它对白血病细胞的影响，发现在100 nM或更低的浓度下，它有效地诱导各种白血病细胞系和原发性急性髓细胞白血病（AML）母细胞的凋亡。然后，我们试图确定其作用机制。雷公藤内酯醇诱导caspase依赖性细胞死亡，伴随着XIAP水平的显着下降。强制XIAP过表达减弱雷公藤甲素诱导的细胞死亡。雷公藤内酯醇还降低Mcl-1，但不影响Bcl-2和BCl-X-L水平。Bcl-2过表达抑制雷公藤内酯醇诱导的细胞凋亡。此外，雷公藤甲素诱导线粒体膜电位和细胞色素C释放的损失。Caspase-9基因敲除的细胞是耐药的，而Caspase-8缺陷的细胞是敏感的雷公藤内酯醇，这表明关键的线粒体，但热的死亡受体途径雷公藤内酯醇诱导的细胞凋亡。雷公藤内酯醇也增强其他抗癌药物诱导的细胞死亡。总的来说，我们的研究结果表明，雷公藤甲素降低XIAP和有效地诱导半胱天冬酶依赖性凋亡的白血病细胞介导的线粒体途径在低纳摩尔浓度。雷公藤内酯醇在体外有效的抗白血病活性，值得进一步研究这种化合物用于治疗白血病和其他恶性肿瘤。
Triptolide, a diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook.f, has shown antitumor activities in a broad range of solid tumors. Here, we examined its effects on leukemic cells and found that, at 100 nM or less, it potently induced apoptosis in various leukemic cell lines and primary acute myeloid leukemia (AML) blasts. We then attempted to identify its mechanisms of action. Triptolide induced caspase-dependent cell death accompanied by a significant decrease in XIAP levels. Forced XIAP overexpression attenuated triptolide-induced cell death. Triptolide also decreased Mcl-1 but not Bcl-2 and BCl-X-L levels. Bcl-2 overexpression suppressed triptolide-induced apoptosis. Further, triptolide induced loss of the mitochondrial membrane potential and cytochrome C release. Caspase-9 knock-out cells were resistant, while caspase-8-deficient cells were sensitive to triptolide, suggesting criticality of the mitochondrial but hot the death receptor pathway for triptolide-induced apoptosis. Triptolide also enhanced cell death induced by other anticancer agents. Collectively, our results demonstrate that triptolide decreases XIAP and potently induces caspase-dependent apoptosis in leukemic cells mediated through the mitochondrial pathway at low nanomolar concentrations. The potent antileukemic activity of triptolide in vitro warrants further investigation of this compound for the treatment of leukemias and other malignancies.