Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University, Tokyo 194‑8543, Japan.
Biomedical Laboratory, Department of Research, Kitasato Institute Hospital, Tokyo 108‑8642, Japan.
Oncol Rep. 2020 Feb;43(2):689-699. doi: 10.3892/or.2019.7421. Epub 2019 Nov 28.
Our previous study demonstrated that gemcitabine (GEM), S‑1, and a combination of GEM and S‑1 (GS) induced S‑phase arrest and increased the phosphorylation of checkpoint kinase 1 (Chk1), which is a critical mediator of cell survival under impaired DNA replication, in pancreatic cancer cell lines. The aim of the present study was to investigate the combined effect of the Chk1 inhibitor prexasertib and antitumor drugs (GEM and S‑1) on pancreatic cancer cell line SUIT‑2. Furthermore, we conducted mechanistic analysis of the combined effect. The MTT assay revealed that a combination of prexasertib and GS showed a strong effect. Mechanistic analysis of the combined effect showed effective induction of apoptosis. Furthermore, a combination of prexasertib and GS downregulated the expression of antiapoptotic protein Bcl‑2. Chk1 knockdown with small interfering RNA and GS treatment resulted in strong induction of apoptosis. Our results provide evidence to show that the combination of prexasertib and GS has a strong antitumor effect and effectively induces apoptosis in pancreatic cancer cells through downregulation of the antiapoptotic protein Bcl‑2. Prexasertib could possibly enhance the effects of standard drugs, including GEM, S‑1, and GS, against pancreatic cancer.
我们之前的研究表明，吉西他滨（GEM）、替吉奥（S-1）和吉西他滨联合替吉奥（GS）在胰腺癌细胞系中诱导 S 期停滞并增加检查点激酶 1（Chk1）的磷酸化，Chk1 是在受损的 DNA 复制下细胞存活的关键介质。本研究旨在探讨 Chk1 抑制剂 prexasertib 与抗肿瘤药物（GEM 和 S-1）联合对胰腺癌细胞系 SUIT-2 的联合作用。此外，我们还对联合作用的机制进行了分析。MTT 检测结果表明，prexasertib 和 GS 的联合作用具有很强的效果。联合作用的机制分析表明，能够有效诱导细胞凋亡。此外，prexasertib 和 GS 的联合作用还下调了抗凋亡蛋白 Bcl-2 的表达。用小干扰 RNA 敲低 Chk1 并联合 GS 处理可强烈诱导细胞凋亡。我们的研究结果表明，prexasertib 和 GS 的联合应用具有很强的抗肿瘤作用，通过下调抗凋亡蛋白 Bcl-2 可有效诱导胰腺癌细胞凋亡。Prexasertib 可能增强包括 GEM、S-1 和 GS 在内的标准药物对胰腺癌的疗效。
