CDK4/6 Inhibitor PD 0332991 Sensitizes Acute Myeloid Leukemia to Cytarabine-Mediated Cytotoxicity.
CDK4/6 Inhibitor PD 0332991 Sensitizes Acute Myeloid Leukemia to Cytarabine-Mediated Cytotoxicity.
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DOI：
10.1158/0008-5472.can-14-2486
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发表时间：
2015-05-01
期刊：
影响因子：
11.2
通讯作者：
Zhou P
中科院分区：
文献类型：
--
作者：
Yang C;Boyson CA;Di Liberto M;Huang X;Hannah J;Dorn DC;Moore MA;Chen-Kiang S;Zhou P
细胞周期蛋白依赖性激酶 (CDK)4 和 CDK6 在人类癌症中经常过度表达或过度激活。因此，靶向 CDK4/CDK6 与细胞毒性杀伤相结合代表了一种合理的癌症治疗方法。通过用 PD 0332991 选择性抑制 CDK4/CDK6，导致早期 G1 阻滞并在 G1 阻滞释放后同步进入 S 期，我们开发了一种新策略来启动急性髓系白血病 (AML) 细胞，以利用阿糖胞苷 (Ara-C) 进行细胞毒性杀伤。这种致敏部分是通过富集 S 期细胞来实现的，这使得 AML 群体最大化，以便 Ara-C 掺入复制 DNA 中，从而引发 DNA 损伤。此外，PD 0332991 通过抑制同源盒 (HOX)A9 癌基因表达，减少其靶标 PIM1 的转录，引发 AML 细胞凋亡。 PIM1 合成减少会减弱 PIM1 介导的促凋亡 BAD 磷酸化，并激活 BAD 依赖性细胞凋亡。在体内，在异种移植 AML 模型中，PD 0332991 及时抑制 CDK4/CDK6 并释放，可响应 Ara-C 剂量减少而显着抑制肿瘤生长。总的来说，这些数据表明选择性和可逆性抑制 CDK4/CDK6 是增强 Ara-C 在减少剂量下杀死 AML 细胞的有效手段，这对治疗无法耐受高剂量 Ara-C 治疗的老年 AML 患者具有重要意义。
Cyclin-dependent kinase (CDK)4 and CDK6 are frequently overexpressed or hyperactivated in human cancers. Targeting CDK4/CDK6 in combination with cytotoxic killing therefore represents a rational approach to cancer therapy. By selective inhibition of CDK4/CDK6 with PD 0332991, which leads to early G1 arrest and synchronous S phase entry upon release of the G1 block, we have developed a novel strategy to prime acute myeloid leukemia (AML) cells for cytotoxic killing by cytarabine (Ara-C). This sensitization is achieved in part through enrichment of S-phase cells, which maximizes the AML populations for Ara-C incorporation into replicating DNA to elicit DNA damage. Moreover, PD 0332991 trigged apoptosis of AML cells through inhibition of the homeobox (HOX)A9 oncogene expression, reducing the transcription of its target PIM1. Reduced PIM1 synthesis attenuates PIM1-mediated phosphorylation of the pro-apoptotic BAD and activates BAD-dependent apoptosis. In vivo, timely inhibition of CDK4/CDK6 by PD 0332991 and release profoundly suppresses tumor growth in response to reduced doses of Ara-C in a xenograft AML model. Collectively, these data suggest selective and reversible inhibition of CDK4/CDK6 as an effective means to enhance Ara-C killing of AML cells at reduced doses, which has implications for the treatment of elderly AML patients who are unable to tolerate high dose Ara-C therapy.