Evaluation of Cardiotoxicity by Anticancer Drugs Focusing on Mitochondrial Function

DOI
  • KONDO Moe
    Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
  • NAKAMURA Yuya
    Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
  • KATO Yuri
    Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
  • FUKATA Mitsuhiro
    Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
  • MI Xinya
    Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
  • ITO Tomoya
    Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
  • NISHIMURA Akiyuki
    National Institute for Physiological Sciences and Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences (NINS), Okazaki, Japan
  • AKASHI Koichi
    Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  • KANDA Yasunari
    Division of Pharmacology, National Institute of Health Sciences (NIHS), Kanagawa, Japan
  • NISHIDA Motohiro
    Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan National Institute for Physiological Sciences and Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences (NINS), Okazaki, Japan

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Other Title
  • ミトコンドリア機能に着目した抗がん剤の心毒性評価

Description

<p>The number of cancer patients worldwide is increasing every year. On the other hand, there are still many unknowns regarding the development of cardiovascular disease in cancer patients. Osimertinib is used for treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer and significantly improves the prognosis. However, heart failure is observed in 1-5% of patients during treatment and QT prolongation in 10%, with a lethal course in some cases, but the mechanism of cardiotoxicity caused by osimertinib has not been elucidated.</p><p>In this study, we focused on the mitochondria of human iPS-derived cardiomyocytes (hiPSC-CMs) to analyze the cardiotoxicity mechanism of osimertinib. Exposure of hiPSC-CMs to anticancer drugs (osimertinib, doxorubicin, and trastuzumab) induced mitochondrial hyperfission and suppressed respiratory capacity. Our laboratory has previously found that sulfur metabolism plays an important role in maintaining mitochondrial quality in cardiomyocytes. When sulfur molecular donors (Na2S, Na2S2, and Na2S3) were added, Na2S most strongly inhibited osimertinib-induced mitochondrial dysfunction. Intracellular imaging using a sulfur molecular detection probe showed that osimertinib reduced intracellular H2S concentrations, which were restored by Na2S exposure.</p><p>These results indicate that osimertinib reduces intracellular H2S levels concurrently with mitochondrial dysfunction in myocardium. Our results also indicate that maintenance of intracellular H2S levels may contribute to the mitigation of osimertinib cardiotoxicity.</p>

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