School of Life Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
Oncol Rep. 2018 Mar;39(3):1322-1330. doi: 10.3892/or.2017.6168. Epub 2017 Dec 20.
Inhibition of checkpoint kinase 1 (CHK1) is a promising therapeutic strategy to increase the effectiveness of DNA-damaging drugs in pancreatic cancer. However, owing to the multiple roles of CHK1 in the DNA damage response (DDR) pathway, the molecular mechanism of chemosensitization by CHK1 inhibitors is not definitive. In the present study, we explored the antitumor mechanism of LY2603618, a specific CHK1 inhibitor, alone or in combination with gemcitabine in 5 pancreatic cancer cell lines. LY2603618 treatment of the pancreatic cancer cell lines resulted in growth inhibition, with IC50 values ranging from 0.89 to 2.75 µM, but limited cell death. Importantly, treatment of pancreatic cancer cell lines with LY2603618 reduced the levels of pCDC25C, pCDK1, and pCDK2, accompanied by DNA damage and RRM1/2 downregulation. Furthermore, LY2603618 synergized with gemcitabine treatment to induce growth inhibition and apoptosis in pancreatic cancer cells. Mechanistic investigations showed that gemcitabine sensitization by CHK1 inhibition was associated with CDK‑dependent RRM1/2 downregulation and DNA damage enhancement. These findings provide a basis for further development of combining CHK1 inhibitors and gemcitabine to treat pancreatic cancer.
抑制检查点激酶 1（CHK1）是提高胰腺癌中 DNA 损伤药物疗效的一种有前途的治疗策略。然而，由于 CHK1 在 DNA 损伤反应（DDR）途径中具有多种作用，CHK1 抑制剂的化学增敏作用的分子机制尚不确定。在本研究中，我们探讨了特异性 CHK1 抑制剂 LY2603618 单独或与吉西他滨联合用于 5 种胰腺癌细胞系的抗肿瘤机制。LY2603618 处理胰腺癌细胞系导致生长抑制，IC50 值范围为 0.89 至 2.75 μM，但细胞死亡有限。重要的是，LY2603618 处理胰腺癌细胞系可降低 pCDC25C、pCDK1 和 pCDK2 的水平，并伴有 DNA 损伤和 RRM1/2 下调。此外，LY2603618 与吉西他滨联合治疗可协同抑制胰腺癌细胞的生长和凋亡。机制研究表明，CHK1 抑制增强吉西他滨敏感性与 CDK 依赖性 RRM1/2 下调和 DNA 损伤增强有关。这些发现为进一步开发 CHK1 抑制剂和吉西他滨联合治疗胰腺癌提供了依据。
