Prexasertib increases the sensitivity of pancreatic cancer cells to gemcitabine and S‑1.

Abstract	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.
Authors	Yoshihito Morimoto, Kimihiko Takada, Osamu Takeuchi, Akinori Takagi, Kazuhiro Watanabe, Masayoshi Hirohara, Tomoyuki Hamamoto, Yutaka Masuda
Journal	Oncology reports (Oncol Rep) Vol. 43 Issue 2 Pg. 689-699 (02 2020) ISSN: 1791-2431 [Electronic] Greece
PMID	31789403 (Publication Type: Journal Article)
Chemical References	BCL2 protein, human Drug Combinations Proto-Oncogene Proteins c-bcl-2 Pyrazines Pyrazoles prexasertib Deoxycytidine S 1 (combination) Tegafur Oxonic Acid Gemcitabine
Topics	Cell Line, Tumor Cell Proliferation (drug effects) Cell Survival (drug effects) Deoxycytidine (analogs & derivatives, pharmacology) Down-Regulation Drug Combinations Drug Synergism Gene Expression Regulation, Neoplastic (drug effects) Humans Oxonic Acid (pharmacology) Pancreatic Neoplasms (drug therapy, metabolism) Proto-Oncogene Proteins c-bcl-2 (metabolism) Pyrazines (pharmacology) Pyrazoles (pharmacology) Tegafur (pharmacology) Gemcitabine

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