ReferenceID 1993
Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway
Phytomedicine
Background: As one of the most classic antineoplastic agents, doxorubicin (Dox) is extensively used to treat a wide range of cancers. Nevertheless, the clinical outcomes of Dox-based therapies are severely hampered due t
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Record Fields
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- Reference Id
- 1993
- Evidence Id
- 18583
- Core Evidence Id
- 18583
- Source Reference Id
- 4007
- Herb2 Reference Id
- HBREF004804
- Subject Paper Key
- HBIN028184_36070662
- Pubmed Id
- 36070662
- Doi
- 10.1016/j.phymed.2022.154407
- Paper Title
- Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway
- Paper Abstract
- Background: As one of the most classic antineoplastic agents, doxorubicin (Dox) is extensively used to treat a wide range of cancers. Nevertheless, the clinical outcomes of Dox-based therapies are severely hampered due to the significant cardiotoxicity. Glycyrrhetinic acid (GA) is the major biologically active compound of licorice, one of the most well-known food additives and medicinal plants in the world. We previously demonstrated that GA has the potential capability to protect mice from Dox-induced cardiac injuries. However, the underlying cardioprotective mechanism remains unexplored. Purpose: To investigate the cardioprotective benefits of GA against Dox-induced cardiotoxicity and to elucidate its mechanisms of action. Study design/methods: H9c2 cardiomyoblasts and AC16 cardiomyocytes were used as the cell models in vitro. A transgenic zebrafish model and a 4T1 mouse breast cancer model were applied to explore the cardioprotective effects of GA in vivo. Results: In vitro, GA inhibited Dox-induced cell death and LDH release in H9c2 and AC16 cells without affecting the anti-cancer effects of Dox. GA significantly alleviated Dox-induced ROS generation, mitochondrial dysfunction, and apoptosis in H9c2 cells. Moreover, GA abolished the expression of pro-apoptotic proteins and restored Nrf2/HO-1 signaling pathway in Dox-treated H9c2 cells. On the contrary, Nrf2 knockdown strongly abrogated the cardioprotective effects of GA on Dox-treated H9c2 cells. In vivo, GA attenuated Dox-induced cardiac dysfunction by restoring stroke volume, cardiac output, and fractional shortening in the transgenic zebrafish embryos. In a 4T1 mouse breast cancer model, GA dramatically prevented body weight loss, attenuated cardiac dysfunction, and prolonged survival rate in Dox-treated mice, without compromising Dox's anti-tumor efficacy. Consistently, GA attenuated oxidative injury, reduced cardiomyocytes apoptosis, and restored the expressions of Nrf2 and HO-1 in Dox-treated mouse hearts. Conclusion: GA protects against Dox-induced cardiotoxicity by suppressing oxidative stress, mitochondrial dysfunction, and apoptosis via upregulating Nrf2/HO-1 signaling pathway. These findings could provide solid evidence to support the further development of GA as a feasible and safe adjuvant to Dox chemotherapy for overcoming Dox-induced cardiotoxicity.
- Journal
- Phytomedicine
- Publish Year
- 2022
- Experiment Subject
- mouse; 4t1 mouse breast cancer model; ac16 cardiomyocytes; ac16 cells; dox-treated h9c2 cells; h9c2; h9c2 cardiomyoblasts; h9c2 cells; zebrafish
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Cancers; Cardiac Dysfunction; Mitochondrial Dysfunction; Dox-induced Cardiotoxicity; 4t1 Mouse Breast Cancer; Dox-induced Cardiac Injuries; Breast Cancer
- Paper Title Cn
- Paper Title En
- Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway
- Bilingual Status
- semi_complete