Characterization of cancer cells highly sensitive to the natural compound AusD

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07037
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Tokyo University of Science
• Principal Investigator: Sadaie Mahito 東京理科大学, 理工学部応用生物科学科, 准教授 (70415173)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: austocystin D / シトクロムP450 / 細胞毒性 / プロドラッグ / 骨肉腫 / がん

Outline of Final Research Achievements

Austocystin D (AD) is a natural compound that causes cytochrome P450 (CYP) monooxygenase-dependent DNA damage and growth inhibition in some cancer cell lines. Cells highly sensitive to this compound tend to express high levels of CYP2J2, but it is not clear whether CYP2J2 is required for the cytotoxicity of this compound. In the present study, we showed that knockdown and overexpression of CYP2J2 alleviated and enhanced both AD sensitivity and DNA damage induction, respectively. Overexpression of CYP2J2, which lacks enzymatic activity, did not increase susceptibility to AD. Screening for genes involved in AD cytotoxicity identified those involved in CYPs activation. These results indicate that CYP2J2 and its enzymatic activity are required for AD cytotoxicity. AD metabolism by CYP2J2 may confer the cytotoxicity. AD could be used as a cytotoxic prodrug for cancer therapy, and the high CYP2J2 expression level possibly be used as a biomarker for cells in which this compound is effective.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究で得られた結果は、CYP2J2とその酵素活性がaustocystin Dの細胞毒性に必要であることを示している。先行研究で得られた知見と総合すると、CYP2J2によるaustocystin Dの代謝がこの細胞毒性をもたらすと考えられる。Austocystin Dは、がん治療のためのプロドラッグとして利用できる可能性があり、CYP2J2発現レベルの高さは、この化合物が効果を発揮できる細胞のバイオマーカーとして使用される可能性がある。