ドキソルビシンはミトコンドリア呼吸を阻害することで致死的心筋ダメージを生ずる

• Published in: 日本薬理学会年会要旨集 p. 1-O-023
• Main Authors: 佐藤, 岳哉, 戸田, 法子, 山内, 正憲, 阿部, 高明
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2022
• Subjects: anticarcinogenic agent; ATP; cardiac myocyte; mitochondria
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.95.0_1-O-023

Doxorubicin (Dox) is one of the practical anti-cancer agents against various tumor cell types. Unfortunately, the use of dox has been hampered due to the life-threatening cardiotoxic damage such as lethal cardiomyopathy it has caused. Mitochondria are double-membrane organelles that play a critical role in cellular homeostases, like ATP supply by oxidative phosphorylation. Many reports suggested that Dox impairs mitochondrial function that causes cardiomyopathy. However, the effect of Dox on oxidative phosphorylation has remained elusive. To confirm the effects of Dox on mitochondrial oxidative phosphorylation, we evaluated the effect of Dox on rat embryonic cardiomyoblast H9c2 cells by measuring oxygen consumption rate (OCR). Administration of 1 µM Dox caused significant decreases in the basal OCR. The addition of 1 µM Dox in the presence of oligomycin exhibited a significant increase of OCR compared to that without Dox, suggesting that Dox damaged regulation of the mitochondrial respiratory system. FCCP treatment with 1 µM Dox caused a significant reduction of the maximal respiratory. We also evaluated the extracellular acidification rate (ECAR). Administration of 1 µM Dox caused a significant increase or showed a tendency to increase in the basal ECAR and the presence of oligomycin, but not in the presence of FCCP. These results indicate that Dox impaired the mitochondrial respiration system and induced the metabolic shift of the cells in the presence of 1 µM of Dox occurred in the basal condition from oxidative phosphorylation to a glycolytic pathway to produce ATP.