Department of Urology, National Defense Medical College, Tokorozawa, Japan.
PLoS One. 2022 Apr 12;17(4):e0266476. doi: 10.1371/journal.pone.0266476. eCollection 2022.
The ataxia telangiectasia and rad3-related-checkpoint kinase 1 (ATR-CHK1) pathway is involved in DNA damage responses in many cancer cells. ATR inhibitors have been used in clinical trials in combination with radiation or chemotherapeutics; however, their effects against bladder cancer remain unclear. Here, the efficacy of combining gemcitabine with the novel ATR inhibitor AZD6738 was investigated in vitro in three bladder cancer cell lines (J82, T24, and UM-UC-3 cells). The effects of gemcitabine and AZD6738 on cell viability, clonogenicity, cell cycle, and apoptosis were examined. The combined use of gemcitabine and AZD6738 inhibited the viability and colony formation of bladder cancer cells compared to either treatment alone. Gemcitabine (5 nM) and AZD6738 (1 μM) inhibited cell cycle progression, causing cell accumulation in the S phase. Moreover, combined treatment enhanced cleaved poly[ADP-ribose]-polymerase expression alongside the number of annexin V-positive cells, indicating apoptosis induction. Mechanistic investigations showed that AZD6738 treatment inhibited the repair of gemcitabine-induced double-strand breaks by interfering with CHK1. Combining AZD6738 with gemcitabine could therefore be useful for bladder cancer therapy.
共济失调毛细血管扩张症和 Rad3 相关检查点激酶 1（ATR-CHK1）通路参与许多癌细胞的 DNA 损伤反应。ATR 抑制剂已在临床试验中与放射治疗或化学疗法联合使用；然而，它们对膀胱癌的作用仍不清楚。在此，研究了在三种膀胱癌细胞系（J82、T24 和 UM-UC-3 细胞）中联合使用吉西他滨和新型 ATR 抑制剂 AZD6738 的体外疗效。检测了吉西他滨和 AZD6738 对细胞活力、集落形成、细胞周期和细胞凋亡的影响。与单独治疗相比，吉西他滨和 AZD6738 的联合使用抑制了膀胱癌细胞的活力和集落形成。吉西他滨（5 nM）和 AZD6738（1 μM）抑制细胞周期进程，导致 S 期细胞积累。此外，联合治疗增强了裂解的多聚[ADP-核糖]聚合酶的表达以及 Annexin V 阳性细胞的数量，表明诱导细胞凋亡。机制研究表明，AZD6738 通过干扰 CHK1 抑制了吉西他滨诱导的双链断裂的修复。因此，AZD6738 与吉西他滨联合使用可能对膀胱癌治疗有用。
