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首页> 外文期刊>Blood: The Journal of the American Society of Hematology >BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38- cells, through activation of protein kinase Cbeta.
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BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38- cells, through activation of protein kinase Cbeta.

机译:BMS-214662通过激活蛋白激酶Cbeta诱导慢性骨髓性白血病(CML)干/祖细胞(包括CD34 + 38-细胞)中的线粒体凋亡。

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摘要

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder maintained by cancer stem cells. To target this population, we investigated the mechanism of action of BMS-214662, developed as a farnesyl transferase inhibitor (FTI) and unique in inducing apoptosis in these cells. By contrast, a related congener and equally effective FTI, BMS-225975 does not induce apoptosis, indicating a novel mechanism of action. BMS-214662 significantly and selectively induced apoptosis in primitive CD34(+)38(-) CML compared with normal cells. Apoptosis proceeded via the intrinsic pathway: Bax conformational changes, loss of mitochondrial membrane potential, generation of reactive oxygen species, release of cytochrome c, and caspase-9/3 activation were noted. Up-regulation of protein kinase Cbeta (PKCbeta), down-regulation of E2F1, and phosphorylation of cyclin A-associated cyclin-dependent kinase 2 preceded these changes. Cotreatment of CML CD34(+) and CD34(+)38(-) cells with PKC modulators, bryostatin-1, or hispidin markedly decreased these early events and the subsequent apoptosis. None of these events was elicited by BMS-214662 in normal CD34(+) cells or by BMS-225975 in CML CD34(+) cells. These data suggest that BMS-214662 selectively elicits a latent apoptotic pathway in CML stem cells that is initiated by up-regulation of PKCbeta and mediated by Bax activation, providing a molecular framework for development of novel therapeutics.
机译:慢性粒细胞白血病(CML)是由癌症干细胞维持的造血干细胞疾病。为了靶向该人群,我们研究了BMS-214662的作用机理,它是作为法呢基转移酶抑制剂(FTI)开发的,并且在诱导这些细胞的凋亡中具有独特性。相比之下,一个相关的同类同等有效的FTI BMS-225975不会诱导细胞凋亡,这表明它具有新的作用机制。与正常细胞相比,BMS-214662显着并选择性地诱导原始CD34(+)38(-)CML中的细胞凋亡。凋亡通过内在途径进行:注意到Bax构象变化,线粒体膜电位丧失,活性氧生成,细胞色素c释放和caspase-9 / 3活化。在这些变化之前,蛋白激酶Cbeta(PKCbeta)的上调,E2F1的下调和细胞周期蛋白A相关的细胞周期蛋白依赖性激酶2的磷酸化。 CML CD34(+)和CD34(+)38(-)细胞与PKC调节剂,bryostatin-1或hispidin的共处理显着降低了这些早期事件和随后的细胞凋亡。 BMS-214662在正常CD34(+)细胞中或BMS-225975在CML CD34(+)细胞中均未引发这些事件。这些数据表明,BMS-214662在CML干细胞中选择性引发潜在的凋亡途径,该途径由PKCbeta的上调引发并由Bax激活介导,为新型治疗药物的开发提供了分子框架。

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