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Updated: Oct 19, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Protective effect of limonin against doxorubicin-induced cardiotoxicity via activating nuclear factor - like 2 and
Jie Deng1, Min Huang2, Hao Wu1
1Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
Abstract:
The anti-tumor and anti-inflammatory effects of limonin have been established, here, we aim to explore whether limonin can induce protective effects against doxorubicin (DOX)-mediated cardiotoxicity which limits its clinical application. We found that limonin attenuated DOX-mediated cytoxicology of myocardial cell line H9C2 by measuring cell viability and reactive oxygen species (ROS) level. Additionally, limonin ameliorates DOX-induced cardiac injury in rat by examining the activity of lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) concentration, and histopathological changes. Mechanistically, it was shown that limonin partially abrogated the inhibition of Nuclear factor - like 2 and Sirtuin 2 signaling induced by DOX. Furthermore, limonin-mediated protective effects on DOX-mediated cytoxicology of H9C2 were rescued by a Sirt2-specific inhibitor or siRNA against Sirt2. Thus, this work reveals that limonin can suppress DOX-mediated cardiotoxicity by activating Nrf2 and Sirt2 signaling.
Insights
Limonin protects against doxorubicin-induced cardiotoxicity by activating Nrf2 and Sirtuin 2 signaling pathways. This study reveals limonin
Area of Science:
- Pharmacology
- Cardiovascular Research
- Natural Products Chemistry
Background:
- Doxorubicin (DOX) is a potent chemotherapy agent with dose-limiting cardiotoxicity.
- Limonin, a citrus fruit compound, exhibits anti-tumor and anti-inflammatory properties.
- The protective effects of limonin against DOX-induced cardiotoxicity are largely unexplored.
Purpose of the Study:
- To investigate the potential protective effects of limonin against doxorubicin-mediated cardiotoxicity.
- To elucidate the underlying molecular mechanisms of limonin's cardioprotective action.
Main Methods:
- In vitro: H9C2 myocardial cell line treated with DOX and limonin, assessing cell viability and reactive oxygen species (ROS) levels.
- In vivo: Rat model of DOX-induced cardiotoxicity, evaluating cardiac injury markers (LDH, SOD, GSH, GSH-Px, MDA) and histopathology.
- Mechanistic studies: Investigating the impact of limonin on Nuclear factor-like 2 (Nrf2) and Sirtuin 2 (Sirt2) signaling pathways.
Main Results:
- Limonin attenuated DOX-induced cytotoxicity in H9C2 cells, reducing ROS levels.
- Limonin ameliorated cardiac injury in rats, improving antioxidant enzyme activity and reducing lipid peroxidation.
- Limonin partially reversed DOX-induced inhibition of Nrf2 and Sirt2 signaling.
- Sirt2 inhibition or knockdown abolished the protective effects of limonin.
Conclusions:
- Limonin demonstrates significant protective effects against doxorubicin-induced cardiotoxicity in both cellular and animal models.
- The cardioprotective mechanism of limonin involves the activation of Nrf2 and Sirt2 signaling pathways.
- Limonin holds potential as a therapeutic agent to mitigate doxorubicin-induced heart damage.
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