2. Academic Validation
  3. The citrus flavonoid nobiletin prevents the development of doxorubicin-induced heart failure by inhibiting apoptosis

The citrus flavonoid nobiletin prevents the development of doxorubicin-induced heart failure by inhibiting apoptosis

  • J Pharmacol Sci. 2025 Jun;158(2):84-94. doi: 10.1016/j.jphs.2025.03.011.
Yoichi Sunagawa 1,  Sonoka Iwashimizu 2,  Masaya Ono 2,  Saho Mochizuki 2,  Kenshiro Iwashita 3,  Rina Sato 3,  Satoshi Shimizu 4,  Masafumi Funamoto 5,  Kana Shimizu 5,  Toshihide Hamabe-Horiike 1,  Yasufumi Katanasaka 1,  Akira Murakami 6,  Tomohiro Asakawa 7,  Makoto Inai 8,  Toshiyuki Kan 8,  Maki Komiyama 9,  Philip Hawke 10,  Kiyoshi Mori 11,  Yoshiki Arakawa 12,  Koji Hasegawa 5,  Kazuho Sakamoto 3,  Junko Kurokawa 3,  Tatsuya Morimoto 13
Affiliations

Affiliations

  • 1 Department of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan; Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555, Japan; Shizuoka General Hospital, Shizuoka, 420-8527, Japan.
  • 2 Department of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan.
  • 3 Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan.
  • 4 Department of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan; Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555, Japan; Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan.
  • 5 Department of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan; Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555, Japan.
  • 6 Department of Food Science and Nutrition, School of Human Science and Environment, University of Hyogo, Hyogo, Japan.
  • 7 Department of Synthetic Organic & Medicinal Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan; Marine Science and Technology, Tokai University, Shizuoka, 424-8610, Japan.
  • 8 Department of Synthetic Organic & Medicinal Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan.
  • 9 Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555, Japan.
  • 10 Laboratory of Scientific English, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan.
  • 11 Shizuoka General Hospital, Shizuoka, 420-8527, Japan; Graduate School of Public Health, Shizuoka Graduate University of Public Health, Japan, Shizuoka, 420-0881, Japan; Division of Molecular and Clinical Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan.
  • 12 Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
  • 13 Department of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan; Division of Translational Research, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, 612-8555, Japan; Shizuoka General Hospital, Shizuoka, 420-8527, Japan. Electronic address: [email protected].
PMID: 40288827 DOI: 10.1016/j.jphs.2025.03.011
Abstract

Background: The anthracycline Anticancer drug doxorubicin (DOX) induces myocardial cell death and heart failure. The aim of the present study was to investigate whether nobiletin (NOB), a natural flavonoid isolated from citrus peel, has a protective effect against DOX-induced cardiotoxicity.

Methods and results: H9C2 cells were pretreated with 100 μM NOB and then treated with 1 μM DOX. An MTT assay revealed that NOB improved the decreased cell viability induced by DOX. A TUNEL assay showed that NOB treatment improved DOX-induced Apoptosis in H9C2 cells. Western blotting indicated that DOX-induced increases in cleaved Caspase-3 and -9 expression were significantly suppressed by NOB treatment. Motion field imaging of human iPS cell-derived cardiomyocyte sheets showed that NOB significantly suppressed a DOX-induced reduction of their contractile function. Next, to investigate the effect of NOB in vivo, DOX was intraperitoneally administered to mice. Echocardiography showed that oral administration of NOB reduced DOX-induced left ventricular systolic dysfunction, and a TUNEL assay showed that oral administration also inhibited Apoptosis in the mouse heart.

Conclusions: These results indicate that NOB treatment suppressed DOX-induced cardiotoxicity by reducing Apoptosis. Further study of the mechanism of this effect may lead to the development of a novel therapy for DOX-induced heart failure.

Keywords

Apoptosis; Cardiomyopathy; Doxorubicin; Nobiletin; Systolic dysfunction.

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