PDF(Pubmed)
Abstract：
Checkpoint kinase 1 (Chk1) is a key mediator of the DNA damage response that regulates cell cycle progression, DNA damage repair, and DNA replication. Small-molecule Chk1 inhibitors sensitize cancer cells to genotoxic agents and have shown preclinical activity as single agents in cancers characterized by high levels of replication stress. However, the underlying genetic determinants of Chk1-inhibitor sensitivity remain unclear. Although treatment options for advanced colorectal cancer are limited, radiotherapy is effective. Here, we report that exposure to a novel amidine derivative, K1586, leads to an initial reduction in the proliferative potential of colorectal cancer cells. Cell cycle analysis revealed that the length of the G2/M phase increased with K1586 exposure as a result of Chk1 instability. Exposure to K1586 enhanced the degradation of Chk1 in a time- and dose-dependent manner, increasing replication stress and sensitizing colorectal cancer cells to radiation. Taken together, the results suggest that a novel amidine derivative may have potential as a radiotherapy-sensitization agent that targets Chk1.
摘要：
检查点激酶1（Chk1）是调节细胞周期进程的DNA损伤反应的关键介质，DNA损伤修复,和DNA复制。小分子Chk1抑制剂可使癌细胞对基因毒性剂敏感，并在以高水平复制应激为特征的癌症中显示出作为单一药物的临床前活性。然而,Chk1抑制剂敏感性的潜在遗传决定因素仍不清楚.尽管晚期结直肠癌的治疗选择有限，放射治疗是有效的。这里,我们报告说，暴露于一种新型的脒衍生物，K1586导致结直肠癌细胞增殖潜力的初始降低。细胞周期分析显示，由于Chk1不稳定，G2/M期的长度随K1586暴露而增加。暴露于K1586以时间和剂量依赖性方式增强了Chk1的降解，增加复制应激和使大肠癌细胞对辐射敏感。一起来看,结果表明,一种新型脒衍生物可能具有作为靶向Chk1的放疗增敏剂的潜力.
