title: 5‑FU resistance abrogates the amplified cytotoxic effects induced by inhibiting checkpoint kinase 1 in p53‑mutated colon cancer cells.
abstract: The emergence of chemoresistance is a major limitation of current cancer therapies, and checkpoint kinase (Chk1) 1 positively correlates with resistance to chemo‑ or radio‑therapy. Cancer cells lacking p53 pathways are completely dependent on the S and G2/M checkpoints via Chk1; therefore, Chk1 inhibition enhances the cytotoxicity of DNA‑damaging agents only in p53‑deficient cells. However, little is known about the synergistic effect of Chk1 inhibition with 5‑FU, the most frequently used antimetabolite, in chemoresistant colorectal cells. In this study, we found that 5‑FU induced S‑phase arrest only in p53‑deficient colorectal cancer cells. 5‑FU treatment induced DNA damage and activation of ataxia telangiectasia mutated (ATM) and Chk1, leading to S‑phase arrest, and Chk1 inhibition using SB218078 reduced S‑phase arrest and increased apoptosis in the presence of 5‑FU. In contrast, in p53‑deficient, 5‑FU‑resistant (5FUR) colon cancer cells that we developed, 5‑FU enhanced DNA damage but did not induce Chk1/ATM activation or cell cycle arrest. SB218078 in combination with 5‑FU did not induce apoptosis. These results indicate that 5‑FU‑resistance abrogated the anticancer effect amplified by Chk1 inhibition, even in p53‑deficient cancer cells.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Akasaka
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tsujii
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Kondo
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Ying
authors.affiliation: Department of Environmental and Preventive Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Division of Gastroenterology, National Hospital Organization Tokyo Medical Center, Tokyo 152‑8902, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Gastroenterology, Osaka National Hospital, Osaka 540‑0006, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Gastroenterology, Osaka Rosai Hospital, Sakai, Osaka 591‑8025, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tsujii
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Maekawa
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Fujinaga
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Shiraishi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hiyama
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Shinzaki
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Watabe
authors.affiliation: Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560‑8565, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nishida
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Iijima
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000470:Alkaloids / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000627:therapeutic use*; D019073:HT29 Cells; D006801:Humans; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C404329:SB 218078; D005472:Fluorouracil