Flavopiridol and histone deacetylase inhibitors promote mitochondrial injury and cell death in human leukemia cells that overexpress Bcl-2 (Retracted article. See vol. 95, pg. 335, 2019)
Flavopiridol and histone deacetylase inhibitors promote mitochondrial injury and cell death in human leukemia cells that overexpress Bcl-2 (Retracted article. See vol. 95, pg. 335, 2019)
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DOI：
10.1124/mol.105.016154
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发表时间：
2006-01-01
影响因子：
3.6
通讯作者：
Grant, S
中科院分区：
文献类型：
--
作者：
Dasmahapatra, G;Almenara, JA;Grant, S
在异位表达Bcl-2/Bcl-x（L）的人白血病细胞（U937和HL-60）和原代AML细胞中检测了细胞周期蛋白依赖性激酶（CDK）抑制剂flavopiridol和组蛋白脱乙酰酶（HDAC）抑制剂（辛二酰苯胺羟肟和丁酸钠）之间的相互作用。Flavopiridol与HDAC抑制剂联合给药可协同增强野生型和Bcl-2或Bcl-x（L）过表达细胞的线粒体损伤（细胞色素c、第二类caspase衍生激活剂/低pI的直接IAP结合蛋白和凋亡诱导因子释放）、caspase激活、聚（ADP-核糖）聚合酶降解和细胞死亡，并诱导克隆形成的明显丧失。相反，Bcl-2和Bcl-x（L）在暴露于细胞毒性剂1-β-D-阿拉伯呋喃糖基胞嘧啶（ara-C）的细胞中很大程度上阻断了这些事件。显性负Fas相关死亡结构域的强制表达未能保护细胞免受flavopiridol/组蛋白脱乙酰酶抑制剂（HDACI）方案的影响，反对受体途径参与致死。磷酸化环缺失的Bcl-2或缺乏丝氨酸70磷酸化位点的Bcl-2的异位表达，其显著地保护细胞免受阿糖胞苷致死，延迟但不阻止flavopiridol/HDAC诱导的线粒体损伤、细胞死亡或克隆形成性丧失。Bcl-2或Bcl-x（L）的异位表达也不能阻止flavopiridol/HDACI方案诱导Bax的构象变化和线粒体易位，并且其不减弱Bax二聚化。总的来说，这些发现表明，与某些常规的细胞毒性剂如ara-C相反，Bcl-2或Bcl-x（L）的过表达在预防同时受到CDK和HDAC抑制的人白血病细胞中Bax的扰动、线粒体损伤和细胞死亡方面基本上无效。他们还提出了一种可能性，即CDK和HDAC抑制剂组合的策略可能对过度表达Bcl-2或Bcl-x（L）的耐药白血病细胞有效。
Interactions between the cyclin-dependent kinase (CDK) inhibitor flavopiridol and histone deacetylase (HDAC) inhibitors (suberoylanilide hydroxamide and sodium butyrate) were examined in human leukemia cells (U937 and HL-60) ectopically expressing Bcl-2/Bcl-x(L) and in primary AML cells. Coadministration of flavopiridol with HDAC inhibitors synergistically potentiated mitochondrial damage (cytochrome c, second mitochondria-derived activator of caspases/direct IAP binding protein with low pI, and apoptosis-inducing factor release), caspase activation, poly(ADP-ribose) polymerase degradation, and cell death in both wild type and Bcl-2- or Bcl-x(L)-overexpressing cells and induced a pronounced loss of clonogenicity. In contrast, Bcl-2 and Bcl-x(L) largely blocked these events in cells exposed to the cytotoxic agent 1-beta-D-arabinofuranosylcytosine (ara-C). Enforced expression of dominant-negative Fas-associated death domain failed to protect cells from the flavopiridol/histone deacetylase inhibitor (HDACI) regimen, arguing against the involvement of the receptor pathway in lethality. Ectopic expression of a phosphorylation loop-deleted Bcl-2 or Bcl-2 lacking the serine 70 phosphorylation site, which dramatically protected cells from ara-C lethality, delayed but did not prevent flavopiridol/HDAC inhibitor-induced mitochondrial injury, cell death, or loss of clonogenicity. Ectopic expression of Bcl-2 or Bcl-x(L) was also unable to prevent the flavopiridol/HDACI regimen from inducing a conformational change in and mitochondrial translocation of Bax, and it did not attenuate Bax dimerization. As a whole, these findings indicate that in contrast to certain conventional cytotoxic agents such as ara-C, overexpression of Bcl-2 or Bcl-x(L) are largely ineffective in preventing perturbations in Bax, mitochondrial injury, and cell death in human leukemia cells subjected to simultaneous CDK and HDAC inhibition. They also raise the possibility that a strategy combining CDK and HDAC inhibitors may be effective against drug-resistant leukemia cells overexpressing Bcl-2 or Bcl-x(L).