Tozaki Yuri, Aoki Hiromasa, Kato Rina, Toriuchi Kohki, Arame Saki, Inoue Yasumichi, Hayashi Hidetoshi, Kubota Eiji, Kataoka Hiromi, Aoyama Mineyoshi
Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
Department of Cell Signaling, Nagoya City University Graduate School of Pharmaceutical Sciences, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
Cancers (Basel). 2023 Jan 25;15(3):735. doi: 10.3390/cancers15030735.
Genetic abnormalities induce the DNA damage response (DDR), which enables DNA repair at cell cycle checkpoints. Although the DDR is thought to function in preventing the onset and progression of cancer, DDR-related proteins are also thought to contribute to tumorigenesis, tumor progression, and drug resistance by preventing irreparable genomic abnormalities from inducing cell death. In the present study, the combination of ataxia telangiectasia-mutated serine/threonine kinase (ATM) and checkpoint kinase 1 (Chk1) inhibition exhibited synergistic antitumor effects and induced synergistic lethality in colorectal cancer cells at a low dose. The ATM and Chk1 inhibitors synergistically promoted the activation of cyclin-dependent kinase 1 by decreasing the phosphorylation levels of T14 and Y15. Furthermore, the combined treatment increased the number of sub-G1-stage cells, phospho-histone H2A.X-positive cells, and TdT-mediated dUTP nick-end labeling-positive cells among colon cancer cells, suggesting that the therapy induces apoptosis. Finally, the combined treatment exhibited a robust antitumor activity in syngeneic tumor model mice. These findings should contribute to the development of new treatments for colorectal cancer that directly exploit the genomic instability of cancer cells.
基因异常引发DNA损伤反应（DDR），该反应可在细胞周期检查点进行DNA修复。尽管DDR被认为在预防癌症的发生和发展中发挥作用，但DDR相关蛋白也被认为通过阻止无法修复的基因组异常诱导细胞死亡，从而促进肿瘤发生、肿瘤进展和耐药性。在本研究中，共济失调毛细血管扩张症突变的丝氨酸/苏氨酸激酶（ATM）和检查点激酶1（Chk1）抑制剂的联合使用在低剂量时对结肠癌细胞表现出协同抗肿瘤作用并诱导协同致死性。ATM和Chk1抑制剂通过降低T14和Y15的磷酸化水平，协同促进细胞周期蛋白依赖性激酶1的激活。此外，联合治疗增加了结肠癌细胞中亚G1期细胞、磷酸化组蛋白H2A.X阳性细胞和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性细胞的数量，表明该疗法可诱导细胞凋亡。最后，联合治疗在同基因肿瘤模型小鼠中表现出强大的抗肿瘤活性。这些发现应为直接利用癌细胞基因组不稳定性的结直肠癌新治疗方法的开发做出贡献。
