Mechanisms of Action of a Dual Cdc7/Cdk9 Kinase Inhibitor against Quiescent and Proliferating CLL Cells
Mechanisms of Action of a Dual Cdc7/Cdk9 Kinase Inhibitor against Quiescent and Proliferating CLL Cells
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DOI：
10.1158/1535-7163.mct-10-1119
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发表时间：
2011-09-01
影响因子：
5.7
通讯作者：
Santocanale, Corrado
中科院分区：
文献类型：
--
作者：
Natoni, Alessandro;Murillo, Laura S.;Santocanale, Corrado
在慢性淋巴细胞白血病(CLL)中，增殖率和对药物诱导的细胞凋亡的抵抗力被认为是影响治疗结果的重要因素。在这项研究中，我们评估了原型细胞分裂周期激酶7(CDC7)抑制剂PHA-767491的活性和作用机制，该抑制剂不仅可以抑制DNA复制的启动，而且还具有细胞周期蛋白依赖性激酶9(CDK9)的抑制活性。我们已经研究了这种双重的CDC7/CDK9抑制剂在静止的CLL细胞和CLL细胞中的作用，这两种细胞已经被用模拟淋巴结微环境的细胞共培养系统诱导增殖。我们发现，这种最初作为DNA复制抑制剂开发的化合物，无论已知的危险因素如何，在促进从患者外周血中纯化的静止CLL细胞的线粒体依赖性凋亡方面特别活跃。在这种情况下，在细胞凋亡之前，Mcl-1蛋白和转录水平的下降可能是由于CDK9的抑制。在CD154和IL-4的刺激下，CLL细胞变得高度耐药，重新进入细胞周期，重新表达CDC7激酶，这是启动DNA复制的关键分子开关，复制它们的DNA，并进行细胞分裂。在这种情况下，用PHA-767491治疗通过抑制CDC7而取消DNA合成，但在触发细胞死亡方面效果较差，尽管不再检测到Mcl-1蛋白。因此，CDC7/CDK9双重抑制有可能通过两种不同的机制针对静止期和活跃增殖期的CLL人群，并可能成为CLL的一种新的治疗策略。摩尔癌症治疗；10(9)；1624-34。(C)2011年AACR。
In chronic lymphocytic leukemia (CLL) the proliferation rate and resistance to drug-induced apoptosis are recognized as important factors in the outcome of treatment. In this study, we assess the activity and the mechanism of action of the prototype cell division cycle kinase 7 (Cdc7) inhibitor, PHA-767491, which inhibits the initiation of DNA replication but also has cyclin-dependent kinase 9 (Cdk9) inhibitory activity. We have studied the effects of this dual Cdc7/Cdk9 inhibitor in both quiescent CLL cells and CLL cells that have been induced to proliferate using a cellular coculture system that mimics the lymph node microenvironment. We find that this compound, originally developed as a DNA replication inhibitor, is particularly active in promoting mitochondrial dependent apoptosis in quiescent CLL cells purified from peripheral blood of patients regardless of recognized risk factors. In this setting, apoptosis is preceded by a decrease in the levels of Mcl-1 protein and transcript possibly due to inhibition of Cdk9. Following stimulation by CD154 and interleukin-4, CLL cells become highly chemoresistant, reenter into the cell cycle, reexpress Cdc7 kinase, a key molecular switch for the initiation of DNA replication, replicate their DNA, and undergo cell division. In this context, treatment with PHA-767491 abolished DNA synthesis by inhibiting Cdc7 but is less effective in triggering cell death, although Mcl-1 protein is no longer detectable. Thus, dual Cdc7/Cdk9 inhibition has the potential to target both the quiescent and actively proliferating CLL populations through two distinct mechanisms and may be a new therapeutic strategy in CLL. Mol Cancer Ther; 10(9); 1624-34. (C)2011 AACR.