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- Publisher Website: 10.1016/j.phymed.2022.154407
- Scopus: eid_2-s2.0-85137285310
- PMID: 36070662
- WOS: WOS:000863233400008
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Article: Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway
Title | Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway |
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Authors | |
Keywords | Cardiotoxicity Doxorubicin Glycyrrhetinic acid Oxidative stress |
Issue Date | 2022 |
Citation | Phytomedicine, 2022, v. 106, article no. 154407 How to Cite? |
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. |
Persistent Identifier | http://hdl.handle.net/10722/316766 |
ISSN | 2023 Impact Factor: 6.7 2023 SCImago Journal Rankings: 1.267 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Cheng, Y | - |
dc.contributor.author | Wu, X | - |
dc.contributor.author | Nie, X | - |
dc.contributor.author | Wu, Y | - |
dc.contributor.author | Zhang, C | - |
dc.contributor.author | Lee, SMY | - |
dc.contributor.author | Lv, K | - |
dc.contributor.author | Leung, GPH | - |
dc.contributor.author | Fu, C | - |
dc.contributor.author | Zhang, J | - |
dc.contributor.author | Li, J | - |
dc.date.accessioned | 2022-09-16T07:23:01Z | - |
dc.date.available | 2022-09-16T07:23:01Z | - |
dc.date.issued | 2022 | - |
dc.identifier.citation | Phytomedicine, 2022, v. 106, article no. 154407 | - |
dc.identifier.issn | 0944-7113 | - |
dc.identifier.uri | http://hdl.handle.net/10722/316766 | - |
dc.description.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. | - |
dc.language | eng | - |
dc.relation.ispartof | Phytomedicine | - |
dc.subject | Cardiotoxicity | - |
dc.subject | Doxorubicin | - |
dc.subject | Glycyrrhetinic acid | - |
dc.subject | Oxidative stress | - |
dc.title | Natural compound glycyrrhetinic acid protects against doxorubicin-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway | - |
dc.type | Article | - |
dc.identifier.email | Wu, X: raxpwu@hku.hk | - |
dc.identifier.email | Leung, GPH: gphleung@hkucc.hku.hk | - |
dc.identifier.authority | Leung, GPH=rp00234 | - |
dc.identifier.doi | 10.1016/j.phymed.2022.154407 | - |
dc.identifier.pmid | 36070662 | - |
dc.identifier.scopus | eid_2-s2.0-85137285310 | - |
dc.identifier.hkuros | 336794 | - |
dc.identifier.volume | 106 | - |
dc.identifier.spage | article no. 154407 | - |
dc.identifier.epage | article no. 154407 | - |
dc.identifier.isi | WOS:000863233400008 | - |