期刊
PHYTOMEDICINE
卷 106, 期 -, 页码 -出版社
ELSEVIER GMBH
DOI: 10.1016/j.phymed.2022.154407
关键词
Glycyrrhetinic acid; Doxorubicin; Cardiotoxicity; Nrf2; Oxidative stress
资金
- National Natural Science Founda-tion of China [82104462]
- China Postdoctoral Science Foundation [2022M710499]
Glycyrrhetinic acid (GA) protects against doxorubicin-induced cardiotoxicity by suppressing oxidative stress, mitochondrial dysfunction, and apoptosis via upregulating the Nrf2/HO-1 signaling pathway.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据