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

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

doi:10.3892/ijo.2014.2693

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

Authors:
- Tomofumi Akasaka
- Masahiko Tsujii
- Jumpei Kondo
- Yoshito Hayashi
- Jin Ying
- Yuquan Lu
- Motohiko Kato
- Takuya Yamada
- Shunsuke Yamamoto
- Takuya Inoue
- Yoshiki Tsujii
- Akira Maekawa
- Tetsuji Fujinaga
- Eri Shiraishi
- Satoshi Hiyama
- Takahiro Inoue
- Shinichiro Shinzaki
- Kenji Watabe
- Tsutomu Nishida
- Hideki Iijima
- Tetsuo Takehara
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Affiliations: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan, Department of Environmental and Preventive Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan, Division of Gastroenterology, National Hospital Organization Tokyo Medical Center, Tokyo 152‑8902, Japan, Department of Gastroenterology, Osaka National Hospital, Osaka 540‑0006, Japan, Department of Gastroenterology, Osaka Rosai Hospital, Sakai, Osaka 591‑8025, Japan, Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560‑8565, Japan
Published online on: October 6, 2014 https://doi.org/10.3892/ijo.2014.2693
Pages: 63-70

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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.

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