5-FU resistance abrogates the amplified cytotoxic effects induced by inhibiting checkpoint kinase 1 in p53-mutated colon cancer cells

• Published in: International journal of oncology Vol. 46; no. 1; pp. 63 - 70
• Main Authors: AKASAKA, TOMOFUMI, TSUJII, MASAHIKO, KONDO, JUMPEI, HAYASHI, YOSHITO, YING, JIN, LU, YUQUAN, KATO, MOTOHIKO, YAMADA, TAKUYA, YAMAMOTO, SHUNSUKE, INOUE, TAKUYA, TSUJII, YOSHIKI, MAEKAWA, AKIRA, FUJINAGA, TETSUJI, SHIRAISHI, ERI, HIYAMA, SATOSHI, INOUE, TAKAHIRO, SHINZAKI, SHINICHIRO, WATABE, KENJI, NISHIDA, TSUTOMU, IIJIMA, HIDEKI, TAKEHARA, TETSUO
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.01.2015; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: 5-fluorouracil; Alkaloids - therapeutic use; Antineoplastic Agents - therapeutic use; Apoptosis; Cancer therapies; Cell cycle; Cell Cycle - drug effects; Cell division; Checkpoint Kinase 1; Chemotherapy; Chk1; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colorectal cancer; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Drug resistance; Drug Resistance, Neoplasm; Drug therapy; Fluorouracil; Fluorouracil - therapeutic use; Gastric cancer; Health aspects; HT29 Cells; Humans; Kinases; Mutation; p53; Phosphorylation - drug effects; Phosphotransferases; Physiological aspects; Protein Kinase Inhibitors - therapeutic use; Protein Kinases - metabolism; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Tumors; Japan
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2014.2693

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 chemo-resistant 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.