Abstract
Although doxorubicin (DOX) is an efficient chemotherapeutic drug for human tumors, severe cardiotoxicity restricts its clinical use. Cinnamaldehyde (CA), a bioactive component isolated from Cinnamonum cassia, possesses potent anti-oxidative and anti-apoptotic potentials. The major aim of this study was to evaluate the protective role of CA against DOX-induced cardiotoxicity. To this end, cardiomyocyte injury models were developed using DOX-treated H9c2 cells and DOX-treated rats, respectively. Herein, we found that CA treatment increased cardiomyocyte viability and attenuated DOX-induced cardiomyocyte death in vitro. CA further protected rats against DOX-induced cardiotoxicity, as indicated by elevated creatine kinase (CK) and lactate dehydrogenase (LDH) levels, myocardium injury, and myocardial fibrosis. CA alleviated DOX-induced myocardial oxidative stress by regulating reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels. Mechanistically, CA markedly accelerated nuclear translocation of nuclear erythroid factor 2-related factor 2 (Nrf2) and increased heme oxygenase-1 (HO-1) expression. Consequently, CA decreased DOX-induced cardiomyocyte ferroptosis, while Erastin (a ferroptosis agonist) treatment destroyed the effect of CA on increasing cardiomyocyte viability. Taken together, the current results demonstrate that CA alleviates DOX-induced cardiotoxicity, providing a promising opportunity to increase the clinical application of DOX.
Funder
the Collaboration Pilot Project of Clinical Integration of Chinese and Western Medicine in the 2019 Annual of the Shanghai Municipal Health Commission
National Natural Science Foundation of China
Publisher
Public Library of Science (PLoS)
Reference50 articles.
1. Doxorubicin-induced cardiotoxicity;JH Silber;The New England journal of medicine,1995
2. New insights into doxorubicin-induced cardiotoxicity: the critical role of cellular energetics;M Tokarska-Schlattner;Journal of molecular and cellular cardiology,2006
3. AKAP-Lbc mediates protection against doxorubicin-induced cardiomyocyte toxicity;S Caso;Biochimica et biophysica acta Molecular cell research,2017
4. The effects of doxorubicin on cardiac calcium homeostasis and contractile function;K Shinlapawittayatorn;Journal of cardiology,2022
5. FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT;X Zhang;Cell death and differentiation,2020