Pretreatment of 3-MA prevents doxorubicin-induced cardiotoxicity through inhibition of autophagy initiation

Abstract

Anthracycline antineoplastics are effective in the treatment of hematological malignancies and solid tumors. However, the anthracycline-induced cardiotoxicity (AIC) limits their use as chemotherapeutic agents. Autophagy-based therapies have been explored to prevent AIC. Yet, whether inhibition of autophagy during its early stage could alleviate AIC remains unclear. In this study, we firstly observed the activation of autophagy during AIC in both cardiomyocyte cell lines AC16 and H9c2. Moreover, knockdown of Atg7, a key regulatory factor in early autophagy, could ameliorate the effects of DOX-induced AIC. Importantly, the use of early autophagy inhibitor 3-MA protected cardiomyocyte cells from DOX-induced cardiotoxicity in vitro and in a chronic AIC mouse model. Our findings demonstrate that inhibiting early stage of autophagy may be an effective preventative therapeutic strategy to protect cardiac function from AIC.

Keywords: 3-MA; Atg7; Autophagy; Cardiotoxicity; Doxorubicin.