Open Access

ATR inhibitor AZD6738 increases the sensitivity of colorectal cancer cells to 5‑fluorouracil by inhibiting repair of DNA damage

  • Authors:
    • Takuya Suzuki
    • Takahisa Hirokawa
    • Anri Maeda
    • Shinnosuke Harata
    • Kaori Watanabe
    • Takeshi Yanagita
    • Hajime Ushigome
    • Nozomi Nakai
    • Yuzo Maeda
    • Kazuyoshi Shiga
    • Ryo Ogawa
    • Akira Mitsui
    • Masahiro Kimura
    • Yoichi Matsuo
    • Hiroki Takahashi
    • Shuji Takiguchi
  • View Affiliations

  • Published online on: February 21, 2022     https://doi.org/10.3892/or.2022.8289
  • Article Number: 78
  • Copyright: © Suzuki et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The repair of DNA damage caused by chemotherapy in cancer cells occurs mainly at two cell cycle checkpoints (G1 and G2) and is a factor contributing to chemoresistance. Most colorectal cancers harbor mutations in p53, the main pathway involved in the G1 checkpoint, and thus, are particularly dependent on the G2 checkpoint for DNA repair. The present study examined the effect of AZD6738, a specific inhibitor of ataxia telangiectasia mutated and rad3‑related (ATR) involved in the G2 checkpoint, combined with 5‑fluorouracil (5‑FU), a central chemotherapeutic agent, on colorectal cancer cells. Since 5‑FU has a DNA‑damaging effect, its combination with AZD6738 is likely to enhance the therapeutic effect. The effects of the AZD6738/5‑FU combination were evaluated in various colorectal cancer cells (HT29, SW480, HCT116 and DLD‑1 cells) by flow cytometry (HT29 cells), western blotting (HT29 cells) and water‑soluble tetrazolium 1 assays (HT29, SW480, HCT116 and DLD‑1 cells), as well as in an experimental animal model (HT29 cells). In vitro, the AZD6738/5‑FU combination increased the number of mitotic cells according to flow cytometry, decreased the checkpoint kinase 1 phosphorylation levels and increased cleaved caspase‑3 and phosphorylated form of H2A.X variant histone levels according to western blotting, and decreased the proliferation rate of four colon cancer cell lines according to cell viability experiments. In vivo, xenografted colorectal cancer cells treated with the AZD6738/5‑FU combination exhibited a marked decrease in proliferation compared with the 5‑FU alone group. The present results suggested that AZD6738 enhanced the effect of 5‑FU in p53‑mutated colorectal cancer.
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April-2022
Volume 47 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Suzuki T, Hirokawa T, Maeda A, Harata S, Watanabe K, Yanagita T, Ushigome H, Nakai N, Maeda Y, Shiga K, Shiga K, et al: ATR inhibitor AZD6738 increases the sensitivity of colorectal cancer cells to 5‑fluorouracil by inhibiting repair of DNA damage. Oncol Rep 47: 78, 2022.
APA
Suzuki, T., Hirokawa, T., Maeda, A., Harata, S., Watanabe, K., Yanagita, T. ... Takiguchi, S. (2022). ATR inhibitor AZD6738 increases the sensitivity of colorectal cancer cells to 5‑fluorouracil by inhibiting repair of DNA damage. Oncology Reports, 47, 78. https://doi.org/10.3892/or.2022.8289
MLA
Suzuki, T., Hirokawa, T., Maeda, A., Harata, S., Watanabe, K., Yanagita, T., Ushigome, H., Nakai, N., Maeda, Y., Shiga, K., Ogawa, R., Mitsui, A., Kimura, M., Matsuo, Y., Takahashi, H., Takiguchi, S."ATR inhibitor AZD6738 increases the sensitivity of colorectal cancer cells to 5‑fluorouracil by inhibiting repair of DNA damage". Oncology Reports 47.4 (2022): 78.
Chicago
Suzuki, T., Hirokawa, T., Maeda, A., Harata, S., Watanabe, K., Yanagita, T., Ushigome, H., Nakai, N., Maeda, Y., Shiga, K., Ogawa, R., Mitsui, A., Kimura, M., Matsuo, Y., Takahashi, H., Takiguchi, S."ATR inhibitor AZD6738 increases the sensitivity of colorectal cancer cells to 5‑fluorouracil by inhibiting repair of DNA damage". Oncology Reports 47, no. 4 (2022): 78. https://doi.org/10.3892/or.2022.8289