Cancer chemoprevention by using diarylpentanoid analog of curcumin as a functional food

• Project/Area Number: 20K11643
• 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: Akita University
• Principal Investigator: Shibata Hiroyuki 秋田大学, 医学系研究科, 教授 (50260071)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: クルクミン / 制御性T細胞 / 腫瘍免疫 / 機能性食品 / GO-Y022 / 2-deoxy-d-glucose / 乳酸 / クルクミンアナログ / ミトコンドリア / ATP産生 / 食品 / がん免疫 / 発がん予防

Outline of Research at the Start

①試験管内におけるTreg誘導の抑制：マウスの脾臓より制御性T細胞（Treg）を単離する。これにTGF-βを添加し、誘導性Tregを得る。これにDP-CurANAを添加し、Treg誘導の抑制を検証する。
②担癌マウスにDP-CurANAを経口摂取させて腫瘍発生の状態、安全性について調べる。
③担癌マウスにおけるTreg誘導の実態：胃癌モデルマウスGanの腫瘍増大につれて末梢血、胃粘膜、小腸粘膜におけるTregが誘導されるかについて調べる。
④上記の状態で末梢血、胃粘膜、小腸粘膜でのTreg誘導の状態について調べる。また、胃癌において腫瘍免疫を抑制するPD-L1の発現を調べる。

Outline of Final Research Achievements

Regulatory T cells (Treg) can suppress tumor immunity negatively. Pyrolyzed curcumin analog, GO-Y022 is included in food, and can suppress Treg differentiation at 250 nM. Oral administration of GO-Y022 could significantly inhibit gastric cancer growth in the mouse models, where the percentage of Treg was not influenced. This phenomenon was due to the production of lactate from cancer cells. For this inhibition, we used 2-deoxy-d-glucose (2DG) together with GO-Y022, inhibiting Treg induction. As 2DG is an analog of glucose, it is also safe. We can use GO-Y022 with 2DG as a functional food to induce tumor immunity.

Academic Significance and Societal Importance of the Research Achievements

クルクミンの熱変性体であるGO-Y022、そしてグルコースの誘導体である2-deoxy-d-glucoseを併用することで胃癌細胞からの乳酸産生を抑制して制御性T細胞の分化誘導を抑制できることが示された。この低毒性で、食用可能な化合物を機能性食品として用いることで、胃癌細胞と免疫細胞のクロストークを遮断する。こうして、腫瘍が存在する微小環境における負のスパイラルを断ち切ることに成功した。このような毒性のない食品でがん薬物療法や化学発がん予防が実現できる可能性が示された。

Research Products

• [Int'l Joint Research] National Institute of Health(米国)
• [Journal Article] Pyrolyzed deketene curcumin controls regulatory T cell generation and gastric cancer metabolism cooperate with 2-deoxy-d-glucose (2023)
  • Author(s): MaruYama Takashi、Miyazaki Hirofumi、Lim Yun-Ji、Gu Jian、Ishikawa Masaki、Yoshida Taichi、Chen WanJun、Owada Yuji、Shibata Hiroyuki
  • Journal Title: Frontiers in Immunology Volume: 14 Pages: 1049713-1049713
  • DOI: 10.3389/fimmu.2023.1049713
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TGF-β and Cancer Immunotherapy (2022)
  • Author(s): MaruYama Takashi、Chen WanJun、Shibata Hiroyuki
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 45 Issue: 2 Pages: 155-161
  • DOI: 10.1248/bpb.b21-00966
  • NAID: 130008150256
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2022-02-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Curcumin Analog GO-Y030 Controls the Generation and Stability of Regulatory T Cells (2021)
  • Author(s): Takashi MaruYama, Shuhei Kobayashi, Hiroko Nakatsukasa, Yuki Moritoki, Daiki Taguchi, Yoichi Sunagawa, Tatsuya Morimoto, Atsuko Asao, Wenwen Jin, Yuji Owada, Naoto Ishii, Yoshiharu Iwabuchi, Akihiko Yoshimura, WanJun Chen, Hiroyuki Shibata
  • Journal Title: Frontiers in immunology Volume: 12 Pages: 687669-687669
  • DOI: 10.3389/fimmu.2021.687669
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Curcumin analog GO‐Y030 boosts the efficacy of anti‐PD‐1 cancer immunotherapy (2021)
  • Author(s): MaruYama Takashi、Kobayashi Shuhei、Shibata Hiroyuki、Chen WanJun、Owada Yuji
  • Journal Title: Cancer Science Volume: 112 Issue: 12 Pages: 4844-4852
  • DOI: 10.1111/cas.15136
  • Peer Reviewed / Open Access / Int'l Joint Research