Protective effect of limonin against doxorubicin-induced cardiotoxicity via activating nuclear factor - like 2 and Sirtuin 2 signaling pathways

Jie Deng; Min Huang; Hao Wu

doi:10.1080/21655979.2021.1985299

Protective effect of limonin against doxorubicin-induced cardiotoxicity via activating nuclear factor - like 2 and Sirtuin 2 signaling pathways

Bioengineered. 2021 Dec;12(1):7975-7984. doi: 10.1080/21655979.2021.1985299.

Authors

Jie Deng¹, Min Huang², Hao Wu¹

Affiliations

¹ Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
² Department of Geriatrics, 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.

Keywords: Limonin; Nrf2; Sirt2; cardiotoxicity; doxorubicin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cardiotoxicity / drug therapy*
Cardiotoxicity / metabolism
Cell Line
Cell Proliferation / drug effects
Cell Survival / drug effects
Disease Models, Animal
Doxorubicin / adverse effects*
Gene Expression Regulation / drug effects
Limonins / administration & dosage*
Limonins / pharmacology
Male
NF-E2-Related Factor 2 / metabolism*
Rats
Reactive Oxygen Species / metabolism
Signal Transduction / drug effects
Sirtuin 2 / metabolism*

Substances

Limonins
NF-E2-Related Factor 2
Nfe2l2 protein, rat
Reactive Oxygen Species
Sirt2 protein, rat
Doxorubicin
Sirtuin 2
limonin

Grants and funding

This work was supported by the Beijing xisike clinical oncology research foundation(sy2018-249) and the Clinical ability improvement project(JSPH-MB-2020-3).