Catalpol Inhibits Autophagy to Ameliorate Doxorubicin-Induced Cardiotoxicity via the AKT-mTOR Pathway

Abstract

As a kind of anthracycline, doxorubicin (DOX) is commonly used as an antitumor drug, but its clinical application has been greatly hindered due to its severe cardiotoxicity. Hence, in this study, we investigated the role of catalpol (CTP) and its effect on DOX-induced cardiotoxicity.

The cardiac function of mice was evaluated by assessing lactate dehydrogenase, creatine kinase isoenzyme, heart weight to body weight, and heart weight/tibia length levels. Histopathological changes were observed using hematoxylin and eosin staining, and the terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to examine myocardial apoptosis. Superoxide dismutase (SOD) activity, glutathione (GSH), and malondialdehyde (MDA) levels were measured to confirm the changes in oxidative stress. Western blotting showed the levels of autophagy- and pathway-related proteins. Expression of autophagy marker LC3 was examined using immunofluorescence staining.

CTP alleviated DOX-induced cardiac damage in mice. We further observed upregulated SOD and GSH levels, and downregulated MDA level after the CTP treatment in DOX-treated mice, indicating the protective role of CTP against oxidative injury. DOX-induced myocardial apoptosis was also inhibited by CTP treatment in mice. In addition, CTP decreased the levels of Beclin1 and LC3II/LC3I, increased the levels of P62, and activated the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in DOX-treated mice.

CTP ameliorated DOX-induced cardiotoxicity by inhibiting oxidative stress, myocardial apoptosis, and autophagy via the AKT-mTOR pathway.