Caffeine inhibits the checkpoint kinase ATM
Caffeine inhibits the checkpoint kinase ATM
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DOI：
10.1016/s0960-9822(99)80486-2
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发表时间：
1999-10-07
期刊：
影响因子：
9.2
通讯作者：
McGowan, CH
中科院分区：
文献类型：
--
作者：
Blasina, A;Price, BD;McGowan, CH
许多抗癌疗法的基础是使用破坏DNA并因此杀死分裂细胞的遗传毒性剂。预计导致细胞超越DNA损伤检查点的试剂会使细胞对遗传毒性试剂的杀伤敏感。因此，它们已被寻求作为放射治疗和化学治疗的替代物。一种这样的化合物，咖啡因，从DNA的复制和修复中分离细胞周期进程[1，2]。因此，咖啡因可作为模型化合物，用于建立以下原理：可使用超越DNA损伤检查点的药物使细胞对遗传毒性药物的杀伤作用敏感[3]。但是，尽管使用了20多年，咖啡因影响细胞周期和检查点反应的分子机制尚未确定。我们研究了咖啡因对人类细胞中G2/M DNA损伤检查点的影响。我们报告了辐射诱导的激酶Cds 1 [4]（也称为Chk 2 [5]）的激活在体内被咖啡因抑制，ATM激酶活性在体外被咖啡因直接抑制。ATM的抑制提供了DNA损伤检查点反应衰减和咖啡因处理细胞放射敏感性增加的分子解释[6-8]。
The basis of many anti-cancer therapies is the use of genotoxic agents that damage DNA and thus kill dividing cells. Agents that cause cells to override the DNA damage checkpoint are predicted to sensitize cells to killing by genotoxic agents. They have therefore been sought as adjuncts in radiation therapy and chemotherapy. One such compound, caffeine, uncouples cell-cycle progression from the replication and repair of DNA [1,2]. Caffeine therefore serves as a model compound in establishing the principle that agents that override DNA-damage checkpoints can be used to sensitize cells to the killing effects of genotoxic drugs [3]. But despite more than 20 years of use, the molecular mechanisms by which caffeine affects the cell cycle and checkpoint responses have not been identified. We investigated the effects of caffeine on the G2/M DNA-damage checkpoint in human cells. We report that the radiation induced activation of the kinase Cds1 [4] (also known as Chk2 [5]) is inhibited by caffeine in vivo and that ATM kinase activity is directly inhibited by caffeine in vitro. Inhibition of ATM provides a molecular explanation of the attenuation of DNA-damage checkpoint responses and for the increased radiosensitivity of caffeine-treated cells [6-8].