The G2 checkpoint inhibitor CBP-93872 increases the sensitivity of colorectal and pancreatic cancer cells to chemotherapy.
The G2 checkpoint inhibitor CBP-93872 increases the sensitivity of colorectal and pancreatic cancer cells to chemotherapy.
复制标题
DOI：
10.1371/journal.pone.0178221
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Shimada M
中科院分区：
文献类型：
--
作者：
Iwata T;Uchino T;Koyama A;Johmura Y;Koyama K;Saito T;Ishiguro S;Arikawa T;Komatsu S;Miyachi M;Sano T;Nakanishi M;Shimada M
CBP-93872通过抑制共济失调-毛细血管扩张突变(ATM)和ATM和RAD3相关(ATR)激活之间的通路，抑制DNA双链断裂诱导的G2检查点的维持。为了研究CBP-93872的临床应用潜力，我们分析了含铂药物奥沙利铂和顺铂、嘧啶类抗代谢药、吉西他滨和5-氟尿嘧啶(5-FU)与CBP-93872联合应用对结直肠癌和胰腺癌细胞株的杀伤作用。CBP-93872可显著提高癌细胞对多种化疗药物的敏感性，这些药物是通过抑制检查点激活来测试的。因此，我们的结果表明，CBP-93872与已知的化疗药物联合处理可抑制ATR和Chk1的磷酸化，并诱导细胞死亡。
CBP-93872 suppresses maintenance of DNA double-stranded break-induced G2 checkpoint, by inhibiting the pathway between ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) activation. To examine the potential use of CBP-93872 for clinical applications, we analyzed the synergistic effects of platinum-containing drugs, oxaliplatin and cisplatin, pyrimidine antimetabolites, gemcitabine and 5-fluorouracil (5-FU), in combination with CBP-93872, on cell lethality in colorectal and pancreatic cancer cell lines. Treatment with CBP-93872 significantly increased cancer cell sensitivities to various chemotherapeutic agents tested through suppression of checkpoint activation. Our results thus reveal that combination treatment of CBP-93872 with known chemotherapeutic agents inhibits phosphorylation of ATR and Chk1, and induces cell death.