Antitumor effects of lifestyle drugs on colorectal cancer: Involvement of antihypertensive drug ARB as a novel chemopreventive agent

• Project/Area Number: 18K11023
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Kagawa University
• Principal Investigator: Kobara Hideki 香川大学, 医学部附属病院, 講師 (10612476)
• Co-Investigator(Kenkyū-buntansha): 岩間 久和 香川大学, 医学部, 准教授 (20398035) ; 森 宏仁 香川大学, 医学部, 客員教授 (20568844) ; 正木 勉 香川大学, 医学部, 教授 (30335848) ; 千代 大翔 香川大学, 医学部附属病院, 助教 (50769346) ; 藤田 浩二 香川大学, 医学部附属病院, 助教 (50749421) ; 西山 典子 (大森 典子 / 西山典子) 香川大学, 医学部附属病院, 医員 (50613410)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 大腸癌 / 間葉系腫瘍 / 抗腫瘍薬 / 化学予防薬 / テルミサルタン / 新規化学予防薬 / 降圧薬 / ARB / 生活習慣病

Outline of Final Research Achievements

We explored the possibility that the antihypertensive drug telmisartan may have antitumor effects on colorectal cancer. The tumor-suppressive effects observed in colorectal cancer cell lines were not observed in the cell cycle, so the target was changed to gastrointestinal stromal tumors (GIST), a type of colorectal tumor. After confirming its antitumor effect on the GIST-T1 cell line, we found that it suppressed the G0-G1 cell cycle via down-regulation of Cyclin D1. The mechanism of action was thought to be the promotion of AMPKα phosphorylation. Furthermore, GIST-T1 cells treated with telmisartan showed decreased expression of miRNA1307-3p, confirming the antitumor effect mediated by specific microRNAs. Telmisartan may have an antitumor effect on colorectal GIST.

Academic Significance and Societal Importance of the Research Achievements

増加する大腸癌の新規治療薬を模索する中、降圧剤テルミサルタンの大腸癌に対する抗腫瘍効果に関しての可能性を探求した。大腸癌細胞株で確認されたその腫瘍抑制効果は細胞周期でみられなかった。そこで大腸腫瘍の1つである消化管間質性腫瘍（GIST）をターゲットとし、GIST-T1細胞株に対するその抗腫瘍効果を確認後、Cyclin D1の発現低下を介したG0-G1細胞周期を抑制することを発見した。その作用機序は、AMPKαリン酸化の促進が考えられた。テルミサルタンは大腸GISTに抗腫瘍効果を有する可能性が示され、新規治療薬に繋がる研究結果が見出された。

Research Products

• [Journal Article] Antihypertensive drug telmisartan inhibits cell proliferation of gastrointestinal stromal tumor cells in?vitro (2020)
  • Author(s): Kobara Hideki, Fujihara Shintaro, Masaki Tsutomu, et al.
  • Journal Title: Molecular Medicine Reports Volume: 22 Issue: 2 Pages: 1063-1071
  • DOI: 10.3892/mmr.2020.11144
  • Peer Reviewed
• [Journal Article] Telmisartan Inhibits Cell Proliferation and Tumor Growth of Esophageal Squamous Cell Carcinoma by Inducing S-Phase Arrest In Vitro and In Vivo. (2019)
  • Author(s): Matsui T, Chiyo T, Kobara H, Fujihara S, Fujita K, Namima D, Nakahara M, Kobayashi N, Nishiyama N, Yachida T, Morishita A, Iwama H, Masaki T.
  • Journal Title: Int J Mol Sci. Volume: 20 Issue: 13 Pages: 13-13
  • DOI: 10.3390/ijms20133197
  • Peer Reviewed
• [Journal Article] Galectin-9 Induces Mitochondria-Mediated Apoptosis of Esophageal Cancer In Vitro and In Vivo in a Xenograft Mouse Model. (2019)
  • Author(s): Chiyo T, Fujita K, Iwama H, Fujihara S, Tadokoro T, Ohura K, Matsui T, Goda Y, Kobayashi N, Nishiyama N, Yachida T, Morishita A, Kobara H, Mori H, Niki T, Hirashima M, Himoto T, Masaki T.
  • Journal Title: Int J Mol Sci. Volume: 20 Issue: 11 Pages: 11-11
  • DOI: 10.3390/ijms20112634
  • Peer Reviewed / Open Access