Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway

Cheng，Yanfen1; Wu，Xiaoping2; Nie，Xin1; Wu，Yihan1; Zhang，Chen1; Lee，Simon Ming Yuen3; Lv，Kongpeng4; Leung，George Pak Heng2; Fu，Chaomei1; Zhang，Jinming1; Li，Jingjing1,2

2022-11-01

10.1016/j.phymed.2022.154407

PHYTOMEDICINE   Impact Factor & Quartile

0944-7113

1618-095X

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.

Cardiotoxicity Doxorubicin Glycyrrhetinic acid Nrf2 Oxidative stress

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China Postdoctoral Science Foundation[2022M710499];National Natural Science Foundation of China[82104462];

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85137285310

Scopus

1.State Key Laboratory of Southwestern Chinese Medicine Resources,School of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu,China
2.Department of Pharmacology and Pharmacy,Li Ka Shing Faculty of Medicine,The University of Hong Kong,Hong Kong
3.State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences,University of Macau,Macao SAR,China
4.Department of Interventional Radiology,Shenzhen People's Hospital (The Second Clinical Medical College,Jinan University; The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,China

Cheng，Yanfen,Wu，Xiaoping,Nie，Xin,et al. Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway[J]. PHYTOMEDICINE,2022,106.

Cheng，Yanfen.,Wu，Xiaoping.,Nie，Xin.,Wu，Yihan.,Zhang，Chen.,...&Li，Jingjing.(2022).Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway.PHYTOMEDICINE,106.

Cheng，Yanfen,et al."Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway".PHYTOMEDICINE 106(2022).