Correlation of gemcitabine sensitization by Chk1 inhibition with p53 status

Chk1 inhibition can selectively improve gemcitabine sensitivity in p53-deficient cells by checkpoints abrogation throughout the cell cycle. However, the dependency of p53 status is still controversial for predicting the priority of such synergy. This study aimed at expounding the differential therapeutic properties of gemcitabine sensitization by Chk1 inhibition potentially affected by p53 status. We introduced wild-type and hotspot mutant p53 in p53-null H1299 cells, and quantified combination of gemcitabine with two Chk1 inhibitors using Chou–Talalay method. As a result, depletion of p53 preferentially produced synergistic effects. Wild-type and mutant p53 also conferred drug synergy but gradually showed compromised potency of growth inhibition. These data provide increased evidence that p53 status is a weak predictor for identifying an effective synergy, but genetic loss of p53 is relatively favorable for combination treatment. Further efforts on validation in more cell lines and clinical models could improve the predictive validity in this study.

Chk1（细胞周期检查点激酶1，Checkpoint kinase 1）抑制可通过解除细胞周期各阶段的检查点，选择性增强p53缺陷细胞对吉西他滨的敏感性。然而，p53状态对该协同效应优先级的预测价值仍存在争议。本研究旨在阐明受p53状态影响的Chk1抑制增强吉西他滨敏感性的差异化治疗特性。本研究向p53缺失的H1299细胞中导入野生型及热点突变型p53，并采用Chou-Talalay联合指数法对吉西他滨与两种Chk1抑制剂的联合用药效果进行定量分析。结果显示，p53缺失优先产生协同效应；野生型与突变型p53同样可介导药物协同效应，但生长抑制效力逐渐减弱。上述数据进一步证实，p53状态作为有效协同效应的预测标志物其预测能力较弱，但p53基因缺失相对更适配联合治疗方案。未来可通过在更多细胞系及临床模型中开展验证研究，提升本研究结果的预测效度。