Inhibitory targeting of checkpoint kinase signaling overrides radiation-induced cell cycle gene regulation:: a therapeutic strategy in tumor cell radio sensitization?
Inhibitory targeting of checkpoint kinase signaling overrides radiation-induced cell cycle gene regulation:: a therapeutic strategy in tumor cell radio sensitization?
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DOI：
10.1016/j.radonc.2004.07.002
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发表时间：
2004-09-01
影响因子：
5.7
通讯作者：
Andersson, Y
中科院分区：
文献类型：
--
作者：
Ree, AH;Bratland, Å;Andersson, Y
背景和目的：肿瘤细胞对电离辐射的防御反应涉及在细胞周期G（2）检查点的暂时停滞，其由ATM激酶对DNA损伤的反应引发的信号级联激活，如果DNA得到适当修复，最终导致细胞进一步存活的结果。ATM引发的检查点激酶信号传导的抑制性靶向可能定义了一种基于生物学的策略，以克服G（2）期延迟，该延迟阻止DNA损伤后有丝分裂进入，从而增加暴露于电离辐射后有丝分裂细胞死亡的可能性。材料和方法：具有完整或缺陷肿瘤功能的乳腺癌细胞系-抑制蛋白BRCA 1在检查点激酶CHK 1的特异性抑制剂（UCN-01）存在或不存在的情况下暴露于电离辐射，并观察细胞周期分布和G（2）期调节因子的反应谱，结果：G2期特异性polo样激酶1和细胞周期蛋白B1在辐射诱导的G2期细胞聚集之前出现短暂的下调，这需要BRCA 1和CHK 1的完整功能。UCN-01的伴随治疗似乎放大了电离辐射对克隆再生的细胞毒性作用。结论：DNA损伤对细胞周期基因调控信号的效应机制通过检查点激酶网络实现。在目前正在进行早期临床试验测试的分子细胞周期靶向药物中，CHK 1抑制剂可能具有作为放射增敏剂的治疗潜力。(C)2004爱思唯尔爱尔兰有限公司保留所有权利。
Background and purpose: The tumor cell defense response to ionizing radiation involves a temporary arrest at the cell cycle G(2) checkpoint, which is activated by a signaling cascade initiated by the ATM kinase response to DNA damage, ultimately leading to the outcome of further cell survival if the DNA is properly repaired. The inhibitory targeting of the checkpoint kinase signaling elicited by ATM may define a biologically based strategy to override the G(2) phase delay that prevents mitotic entry after DNA damage, thereby increasing the probability of mitotic cell death following exposure to ionizing radiation.Materials and methods: Breast carcinoma cell lines with intact or defective function of the tumor-suppressor protein BRCA1 were exposed to ionizing radiation in the absence or presence of a specific inhibitor (UCN-01) of the checkpoint kinase CHK1, and the response profiles of cell cycle distribution and G(2) phase regulatory factors, as well as the efficiency of clonogenic regrowth, were analyzed.Results: The radiation-induced G(2) phase accumulation was preceded by a transient down-regulation of the G(2) phase-specific polo-like kinase-1 and cyclin B1, which required intact function of both BRCA1 and CHK1. The concomitant treatment with UCN-01 seemed to amplify the cytotoxic effect of ionizing radiation on clonogenic regrowth.Conclusion: The effector mechanism of DNA damage on cell cycle gene regulation signals through the checkpoint kinase network. Among molecular cell cycle-targeted drugs currently in pipeline for testing in early phase clinical trials, CHK1 inhibitors may have therapeutic potential as radiosensitizers. (C) 2004 Elsevier Ireland Ltd. All rights reserved.