RRC ID 67527
Author Akasaka T, Tsujii M, Kondo J, Hayashi Y, Ying J, Lu Y, Kato M, Yamada T, Yamamoto S, Inoue T, Tsujii Y, Maekawa A, Fujinaga T, Shiraishi E, Hiyama S, Inoue T, Shinzaki S, Watabe K, Nishida T, Iijima H, Takehara T.
Title 5‑FU resistance abrogates the amplified cytotoxic effects induced by inhibiting checkpoint kinase 1 in p53‑mutated colon cancer cells.
Journal Int J Oncol
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.
Volume 46(1)
Pages 63-70
Published 2015-1-1
DOI 10.3892/ijo.2014.2693
PMID 25310623
MeSH Alkaloids / therapeutic use* Antineoplastic Agents / therapeutic use* Cell Cycle / drug effects Checkpoint Kinase 1 Colonic Neoplasms / drug therapy* Colonic Neoplasms / genetics Colonic Neoplasms / metabolism Drug Resistance, Neoplasm* Fluorouracil / therapeutic use* HT29 Cells Humans Mutation Phosphorylation / drug effects Protein Kinase Inhibitors / therapeutic use* Protein Kinases / metabolism Tumor Cells, Cultured Tumor Suppressor Protein p53 / genetics
IF 3.899
Human and Animal Cells MKN45(RCB1001)