Study of the COX-independent mechanisms in the efficacy of prevention for colon carcinogenesis by NSAIDs

• Project/Area Number: 17K19829
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Society medicine, Nursing, and related fields
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: TOMOSUGI (HORINAKA) Mano 京都府立医科大学, 医学(系)研究科(研究院), 講師 (80512037)
• Research Collaborator: AONO yuichi
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: がん予防 / 大腸がん / NSAIDs / がん / 予防

Outline of Final Research Achievements

Sulindac sulfone is the metabolite of sulindac, a non-steroidal anti-inflammatory drug (NSAID), without anti-inflammatory activity. Sulindac sulfone has been reported to significantly reduce colorectal adenomatous polyps in clinical trials.
In this study, we showed for the first time that sulindac sulfone directly bound to voltage-dependent anion channel (VDAC) 1 and 2. Moreover, we found that sulindac sulfone induced cell cycle arrest and suppresses the mTORC1 pathway by binding and functionally inhibiting VDACs. There is a possibility that the VDAC might be one of the target molecules of sulindac sulfone for pharmacological actions, including chemopreventive effects against colon cancer.

Academic Significance and Societal Importance of the Research Achievements

本研究成果により、大腸がん予防効果が期待されているスリンダクスルフォンの新たな作用機序が明らかとなった。スリンダクスルフォンはVDAC1とVDAC2を直接の作用分子とし、大腸がん細胞の増殖を停止させている可能性を初めて示すものである。COX阻害作用を有さないスリンダクスルフォンの作用機序が解明されていくことは、さらに今後の大腸がん化学予防研究の発展に向けた貢献が期待できる。

Research Products

• [Journal Article] Sulindac sulfone inhibits the mTORC1 pathway in colon cancer cells by directly targeting voltage-dependent anion channel 1 and 2 (2018)
  • Author(s): Aono Yuichi、Horinaka Mano、Iizumi Yosuke、Watanabe Motoki、Taniguchi Tomoyuki、Yasuda Shusuke、Sakai Toshiyuki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 505 Issue: 4 Pages: 1203-1210
  • DOI: 10.1016/j.bbrc.2018.10.050
  • Peer Reviewed
• [Presentation] 新規スリンダクスルホン結合タンパク質VDACによる細胞周期制御のメカニズムの解析 (2019)
  • Author(s): 青野裕一，堀中真野，飯泉陽介，渡邉元樹，谷口知行，安田周祐，酒井敏行.
  • Organizer: 第18回分子予防環境医学研究会
• [Presentation] スリンダク代謝体の大腸腺腫形成抑制作用における新規標的分子の探索と作用機序の解析 (2019)
  • Author(s): 青野裕一，堀中真野，飯泉陽介，渡邉元樹，谷口知行，安田周祐，酒井敏行.
  • Organizer: 第89回日本衛生学会学術総会
• [Presentation] 食べて防ごう！ がん化学予防への挑戦！ (2018)
  • Author(s): 堀中真野
  • Organizer: おかやまバイオアクティブ研究会第53回シンポジウム
  • Invited