Analysis of neoplastic cell-specific fatal effects with reactive oxygen species abnormality derived from compound from plant species, piperlongumine

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K00537
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Kyoto University
• Principal Investigator: Tano Keizo 京都大学, 複合原子力科学研究所, 准教授 (00183468)
• Co-Investigator(Kenkyū-buntansha): 増永 慎一郎 京都大学, 複合原子力科学研究所, 教授 (80238914)
• Research Collaborator: NAGASAWA Hideko
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: DNA損傷修復 / 細胞内微細環境 / 活性酸素種

Outline of Final Research Achievements

We assessed genotoxic potentials of Piperlongumine (PL) and Tirapazamine (TPZ) by utilizing DT40 cell lines. Our result showed that PL sensitized the cells deficient in homologous recombination related genes. The increase in frequency of the chromosome breaks and the accumulation of the Rad51 protein to chromatin were observed. It indicates that PL is a clastogenic and cytotoxic chemical that induces DSBs. TPZ is converted to a radical intermediate in hypoxia and this intermediate interacts with intracellular macromolecules including DNA. tdp1, tdp2, parp1, and aptx1 cells displayed hyper-sensitivity to TPZ only in hypoxic conditions. These suggest that the accumulations of topo I or topo II-trapped DNA complex and abortive ligation products with 3'-AMP are the potential cause of TPZ-induced killing of hypoxic cells. We conclude that TPZ induces oxidative DNA damage both in normoxia and hypoxia, and introduces abortive topo-DNA complexes and unligatable DNA ends selectively in hypoxia.

Free Research Field

放射線生物学

Academic Significance and Societal Importance of the Research Achievements

腫瘍細胞特異的な致死効果を持つピペロングミンの解析結果は、正常細胞への影響を最小限に抑える新規抗がん剤の開発に繋がることが期待される。また、腫瘍細胞特有の微細環境（低グルコースや低酸素）に着目し、その環境下でのみ細胞致死効果が得られる薬剤の探索も同様の意義を持つと考える。低酸素下で特異的な致死効果をもたらすチラパザミンが、細胞内活性酸素種のアンバランスによりDNA損傷を誘発するとの結果は、腫瘍細胞内微細環境を利用した新規抗がん剤のスクリーニングにヒントを与えるものである。