Approach toward age-related diseases with the use of a new senolytic drugs

• Project/Area Number: 18K15065
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Osaka University
• Principal Investigator: Wakita Masahiro 大阪大学, 微生物病研究所, 特任研究員(常勤) (70794668)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 細胞老化 / セノリティックドラッグ / 炎症 / がん / 加齢 / 老化細胞

Outline of Final Research Achievements

Although cellular senescence acts primarily as a tumor suppression mechanism, the accumulation of senescent cells in vivo eventually exerts deleterious side effects due to inflammatory and/ or tumor-promoting factor secretion. Thus, the development of new drugs that specifically eliminate senescent cells, termed senolysis, is anticipated. In this study, I found that ARV825, which was identified as a promising senolytic drugs in my lab, provokes senolysis due to two independent but integrated pathways: (i) attenuation of non-homologous end joining repair, and (ii) up-regulation of autophagic gene expression. Notably, the elimination of chemotherapy-induced senescent cells by a ARV825 substantially increased the efficacy of chemotherapy against xenograft tumor in immunocompromised mice. These results reveal the vulnerability of senescent cells and open up the possibilities for its control.

Academic Significance and Societal Importance of the Research Achievements

発がんストレスを受けた細胞はがん抑制機構として働く細胞老化を起こすが、近年、この細胞がさまざまな炎症性物質を分泌することにより、がんや神経変性疾患などの加齢性疾患の症状を進行させる慢性炎症に関与することが明らかになりつつある。そこで、老化細胞除去作用を持つセノリティックドラッグの実用化が期待されている。本研究課題では、ARV825がセノリティックドラッグとして作用することで、がん治療へアプローチできる可能性を示した。さらに、老化細胞を細胞死へと誘導する分子メカニズムを明らかにしたことにより、今後さらに安全かつ効果的なセノリティックドラッグの開発へ発展していくことが期待される。

Research Products

• [Journal Article] A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. (2020)
  • Author(s): Wakita M, Takahashi A, Sano O, Loo TM, Imai Y, Narukawa M, Iwata H, Matsudaira T, Kawamoto S, Ohtani N, Yoshimori T, Hara E.
  • Journal Title: Nat Commun Volume: 1935 Issue: 1 Pages: 1935-1935
  • DOI: 10.1038/s41467-020-15719-6
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells (2018)
  • Author(s): Takahashi A, Loo TM, Okada R, Kamachi F, Watanabe Y, Wakita M, Watanabe S, Kawamoto S, Miyata K, Barber GN, Ohtani N, Hara E
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1249-1249
  • DOI: 10.1038/s41467-018-03555-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] High-throughput screening of senolysis drug uncovers cellular vulnerability of senescent cells (2019)
  • Author(s): 脇田将裕
  • Organizer: 2019年度 先端モデル動物支援プラットフォーム 成果発表会
• [Patent(Industrial Property Rights)] BET阻害剤及びその作用機序を利用した老化細胞除去 (2019)
  • Inventor(s): 原英二、脇田将裕、高橋暁子
  • Industrial Property Rights Holder: 原英二、脇田将裕、高橋暁子
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019