Selective Chk1 inhibitors differentially sensitize p53-deficient cancer cells to cancer therapeutics
Selective Chk1 inhibitors differentially sensitize p53-deficient cancer cells to cancer therapeutics
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DOI：
10.1002/ijc.22198
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发表时间：
2006-12-15
影响因子：
6.4
通讯作者：
Zhang, Haiying
中科院分区：
文献类型：
--
作者：
Chen, Zehan;Xiao, Zhan;Zhang, Haiying
大多数癌症治疗剂诱导DNA损伤以杀死细胞。正常的增殖细胞经历细胞周期停滞以响应DNA损伤，从而允许DNA修复以保护基因组。DNA损伤诱导的细胞周期阻滞依赖于进化上保守的信号转导网络，其中Chk 1激酶起着关键作用。在哺乳动物细胞中，p53和RB通路进一步增强细胞周期停滞反应，以防止灾难性的细胞死亡。鉴于大多数肿瘤细胞在p53和RB通路中存在缺陷，肿瘤细胞可能比正常细胞更依赖Chk 1激酶来维持细胞周期停滞。因此，Chk 1抑制可用于特异性地使肿瘤细胞对DNA损伤剂敏感。我们以前已经证明，siRNA介导的Chk 1敲低消除了DNA损伤诱导的检查点，并增强了几种DNA损伤剂在p53缺陷细胞系中的细胞毒性。在这项研究中，我们开发了两种有效的选择性Chk 1抑制剂A-690002和A-641397，并显示这些化合物消除细胞周期检查点并增强拓扑异构酶抑制剂和γ-辐射在p53-缺乏但不存在于不同组织来源的p53-活性细胞中。这些结果表明，基于广泛的肿瘤类型中p53通路的状态，用1种或多种Chk 1抑制剂在增强癌症治疗中实现治疗窗是可行的。(c)2006 Wiley-Liss，Inc.
The majority of cancer therapeutics induces DNA damage to kill cells. Normal proliferating cells undergo cell cycle arrest in response to DNA damage, thus allowing DNA repair to protect the genome. DNA damage induced cell cycle arrest depends on an evolutionarily conserved signal transduction network in which the Chk1 kinase plays a critical role. In mammalian cells, the p53 and RB pathways further augment the cell cycle arrest response to prevent catastrophic cell death. Given the fact that most tumor cells suffer defects in the p53 and RB pathways, it is likely that tumor cells would depend more on the Chk1 kinase to maintain cell cycle arrest than would normal cells. Therefore Chk1 inhibition could be used to specifically sensitize tumor cells to DNA-damaging agents. We have previously shown that siRNA-mediated Chk1 knockdown abrogates DNA damage-induced checkpoints and potentiates the cytotoxicity of several DNA-damaging agents in p53-deficient cell lines-In this study, we have developed 2 potent and selective Chk1 inhibitors, A-690002 and A-641397, and shown that these compounds abrogate cell cycle checkpoints and potentiate the cytotoxicity of topoisomerase inhibitors and gamma-radiation in p53-deficient but not in p53-proficient cells of different tissue origins. These results indicate that it is feasible to achieve a therapeutic window with 1 or more Chk1 inhibitors in potentiation of cancer therapy based on the status of the p53 pathway in a wide spectrum of tumor types. (c) 2006 Wiley-Liss, Inc.