Drug development of new bioactive compounds induced p53-dependent growth suppression

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08512
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: Microbial Chemistry Research Foundation
• Principal Investigator: TATSUDA Daisuke 公益財団法人微生物化学研究会, 微生物化学研究所, 研究員 (20442569)
• Research Collaborator: MOMOSE Isao ; KAWADA Manabu ; OHBA Shunichi ; YOSHIDA Junjiro ; OHISHI Tomokazu ; SAWA Ryuichi ; TAKAHASHI Yuko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 抗腫瘍効果 / p53依存的細胞死

Outline of Final Research Achievements

Mdm2 binds to and ubiquitinates p53, a tumor suppressor, and induces degradation of p53 by 26S proteasome in tumor cells. Suppression of p53 degradation, however, can activate p53, and induce cell cycle arrest and apoptosis. To search for a new activator of the p53-dependent signaling pathway, we screened microbial metabolites using human glioblastoma LNZTA3 cells in which p53 expression can be regulated by tetracycline. As a result of screening, we identified quinofuracins A-E from Staphylotrichumboninense PF1444 and coccoquinones A and B from Staphylotrichum coccosporum PF1460, novel anthraquinone derivatives. Quinofuracins and coccoquionones induced p53-dependent cell death upregulated the expression of p53 and stimulated PARP degradation in p53-expressing LNZTA3 cells. Quinofraciine D specifically bound to several proteins in p53-expressing LNZTA3 cells. In a xenograft model, quinofuracins and coccoquinones suppressed prostate cancer tumor growth.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では我々の見出した新規化合物であるキノフラシンやコッコキノンが特異的な作用によってp53依存的細胞死を誘導することを示唆しており新しい作用機序を持つユニークな化合物として学術的に興味深い成果を得た。またキノフラシンやコッコキノンはin vitroだけでなくin vivoでも抗腫瘍効果を示すことが明らかとなった。このことはこれらの化合物が新しいがん治療薬の開発へとつながる可能性を有しており本研究成果は社会的意義が高いと考えられる。