Caspase-independent cell death in AML: caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis
Caspase-independent cell death in AML: caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis
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DOI：
10.1182/blood-2003-03-0960
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发表时间：
2003-12-01
期刊：
影响因子：
20.3
通讯作者：
Andreeff, M
中科院分区：
文献类型：
--
作者：
Carter, BZ;Kornblau, SM;Andreeff, M
Survivin和XIAP是被称为凋亡抑制因子的蛋白质家族的成员，它们干扰被称为“细胞死亡执行者”的caspase的激活。我们检测了初发急性髓系白血病(AML)细胞中Survivin(n=116)和XIAP(n=172)的表达，并评估了它们的表达对预后的影响。在所有被分析的样品中都检测到了它们。然而，AML患者的细胞遗传学、缓解程度或总存活率之间没有相关性。为了探讨caspase在化疗诱导AML细胞凋亡中的作用，我们用Ara-C、阿霉素、长春新碱和紫杉醇处理OCL-AML3细胞，诱导caspase裂解和凋亡。用PAN-caspase抑制剂阻断caspase激活可消除聚(二磷酸腺苷[ADP]-核糖)聚合酶裂解和DNA断裂，但不能阻止化疗诱导的细胞死亡，也不能抑制或仅部分抑制线粒体细胞色素c、Smac、凋亡诱导因子(AIF)的释放或线粒体膜电位的丧失。抑制caspase也不能在体外保护AML细胞免受化疗诱导的细胞死亡。这些结果表明，Survivin或XIAP的表达水平对AML患者的预后没有影响。虽然抗癌药物可诱导caspase裂解和细胞凋亡，但细胞杀伤不依赖于caspase。这可能部分解释了XIAP和Survivin缺乏对预后的影响，并可能提示AML的细胞死亡机制不依赖于caspase。(C)2003年，由美国血液病学会提供。
Survivin and XIAP, members of the protein family known as the inhibitors of apoptosis, interfere with the activation of caspases, called the "cell death executioners." We examined Survivin (n = 116) and XIAP (n = 172) expression in primary acute myeloid leukemia (AML) blasts and assessed the impact of their expression on prognosis. They were detected in all samples analyzed. However, no correlation was observed with cytogenetics, remission attainment, or overall survival of patients with AML. To investigate the importance of caspases in chemotherapy-induced apoptosis in AML, we treated OCl-AML3 cells with Ara-C, doxorubicin, vincristine, and paclitaxel, which induced caspase cleavage and apoptosis. Blocking of caspase activation by pan-caspase inhibitor abolished poly(adenosine diphosphate [ADP]-ribose) polymerase cleavage and DNA fragmentation but did not prevent chemotherapy-induced cell death and did not inhibit, or only partially inhibited, mitochondrial release of cytochrome c, Smac, apoptosis-inducing factor (AIF), or loss of mitochondrial membrane potential. Caspase inhibition also did not protect AML blasts from chemotherapy-induced cell death in vitro. These results suggest that expression levels of Survivin or XIAP have no prognostic impact in AML patients. Although anticancer drugs induced caspase cleavage and apoptosis, cell killing was caspase independent. This may partially explain the lack of prognostic impact of XIAP and Survivin and may suggest caspase-independent mechanisms of cell death in AML. (C) 2003 by The American Society of Hematology.