Bcl‑xL‑specific BH3 mimetic A‑1331852 suppresses proliferation of fluorouracil‑resistant colorectal cancer cells by inducing apoptosis

Kato,Akira; Takahashi,Hiroki; Asai,Hiroyuki; Uehara,Shuhei; Harata,Shinnosuke; Fujii,Yoshiaki; Watanabe,Kaori; Yanagita,Takeshi; Suzuki,Takuya; Ushigome,Hajime; Shiga,Kazuyoshi; Yamakawa,Yushi; Ogawa,Ryo; Mitsui,Akira; Matsuo,Yoichi; Takiguchi,Shuji

doi:10.3892/or.2024.8859

Bcl‑xL‑specific BH3 mimetic A‑1331852 suppresses proliferation of fluorouracil‑resistant colorectal cancer cells by inducing apoptosis

Authors:
- Akira Kato
- Hiroki Takahashi
- Hiroyuki Asai
- Shuhei Uehara
- Shinnosuke Harata
- Yoshiaki Fujii
- Kaori Watanabe
- Takeshi Yanagita
- Takuya Suzuki
- Hajime Ushigome
- Kazuyoshi Shiga
- Yushi Yamakawa
- Ryo Ogawa
- Akira Mitsui
- Yoichi Matsuo
- Shuji Takiguchi
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Affiliations: Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467‑8601, Japan, Department of Gastroenterological Surgery, Toyokawa City Hospital, Toyokawa, Aichi 442‑8561, Japan
Published online on: December 20, 2024 https://doi.org/10.3892/or.2024.8859
Article Number: 26
Copyright: © Kato et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

BH3 mimetics are small‑molecule inhibitors of the antiapoptotic Bcl‑2 family and have therapeutic efficacy against hematological malignancies. BH3 mimetic A‑1331852 suppresses colorectal cancer cell proliferation. Progressive resistance to the widely used anticancer agent fluorouracil (5‑FU) is a key reason for colorectal cancer recurrence; therefore, the present study tested if A‑1331852 can suppress the proliferation of 5‑FU‑resistant colorectal cancer cells. A 5‑FU‑resistant colorectal cancer cell line was derived from HCT116 cells and compared with the parental line. Expression levels of the antiapoptotic Bcl‑2 proteins Bcl‑xL and myeloid cell leukemia 1 (Mcl‑1) were determined via western blotting, proliferation in the presence of 5‑FU and following small interfering (si)RNA‑mediated Bcl‑xL or Mcl‑1 knockdown was assessed by WST‑1 assay and sensitivity to A‑1331852‑induced apoptosis was assessed via western blotting and DNA fragmentation assay. In addition, a xenograft mouse model of 5‑FU‑resistant colorectal cancer was established via subcutaneous inoculation of 5‑FU‑resistant HCT116 cells to examine the in vivo antitumor efficacy of A‑1331852. Compared with the parental line, 5‑FU‑resistant cells overexpressed Bcl‑xL. Knockdown of Bcl‑xL by siRNA and treatment with A‑1331852 suppressed proliferation and induced the apoptosis of both 5‑FU‑resistant and parental HCT116 cells, but the potency of both effects was stronger in 5‑FU‑resistant than parental HCT116 cells. Furthermore, A‑1331852 suppressed the growth of xenograft tumors derived from 5‑FU‑resistant cells by inducing apoptosis. Overall, the present findings suggested that Bcl‑xL upregulation contributes to 5‑FU resistance of colorectal cancer and targeted inhibition by A‑1331852 may be an effective treatment strategy.

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