Clinical use of the anti-
cancer drug
doxorubicin (DOX) is largely limited due to its severe
cardiotoxicity. Dysregulation of autophagy is implicated in DOX-induced
cardiotoxicity (
DIC). Prior studies have indicated that
Beclin1 and lysosomal-associated membrane proteins-1 (LAMP1) are critical mediators of autophagy. In this work, by assessing autophagic flux in a DOX-stimulated H9C2 model, we observed autolysosome accumulation caused by interruption of autolysosome degradation.
Tanshinone IIA (
TSA) is a well-known small molecule that exerts impressive cardioprotective effects on
heart failure. Here, we investigated the regulation of
TSA in DOX-treated zebrafish, mice, and H9C2 models. Results demonstrated that
TSA remarkably improved heart function and reversed pathological changes in vivo, while
TSA restored autophagic flux by promoting autolysosome degradation and autophagosome formation. Further experiments demonstrated that these effects were mediated through upregulation of
Beclin1 and LAMP1. The mTOR agonist
MHY1485 was shown to abrogate the effect of
TSA via the
UNC-51-like kinase 1 (ULK1)-
Beclin1/TFEB-LAMP1 signaling pathway in vitro, demonstrating that
TSA protects against
DIC by promoting autophagy via the
Beclin1/LAMP1 signaling pathway. We further employed a U87 model to assess whether
TSA would compromise the antitumor activity of DOX. Intriguingly, the co-treatment of
TSA was able to synergistically inhibit proliferative activity. Collectively, in this study we uncover the novel insight that
TSA is able to reduce the
cardiotoxicity of DOX without compromising antitumor activity.