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
  • 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.
Products