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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.
Pubmed ID: 31261758 RIS Download
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View all literature mentionsCell line H9c2(2-1) is a Spontaneously immortalized cell line with a species of origin Rattus norvegicus (Rat)
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsThis polyclonal targets LAMP1
View all literature mentionsThis polyclonal targets Goat anti-Mouse IgG2b heavy chain (HRP) secondary antibody
View all literature mentionsThis polyclonal targets Bcl2
View all literature mentionsThis monoclonal targets SQSTM1 / p62
View all literature mentionsThis polyclonal targets Rabbit Rabbit IgG secondary
View all literature mentionsThis polyclonal targets Tubulin
View all literature mentionsThis polyclonal targets Beclin 1 antibody
View all literature mentionsThis polyclonal targets RPS6KB1
View all literature mentionsThis monoclonal targets GAPDH antibody [6C5]
View all literature mentionsThis monoclonal targets Bax
View all literature mentionsThis polyclonal targets S6K (phospho T389)
View all literature mentionsThis polyclonal targets LC3A/B antibody
View all literature mentionsThis monoclonal targets mTOR
View all literature mentionsThis monoclonal targets ULK1
View all literature mentionsThis monoclonal targets ULK1
View all literature mentionsThis polyclonal targets Phospho-mTOR (Ser2448)
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsOpen source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.
View all literature mentionsOpen source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.
View all literature mentionsThis polyclonal targets Tubulin
View all literature mentionsThis polyclonal targets Goat anti-Mouse IgG2b heavy chain (HRP) secondary antibody
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsThis monoclonal targets SQSTM1 / p62
View all literature mentionsThis polyclonal targets S6K (phospho T389)
View all literature mentionsThis polyclonal targets Rabbit Rabbit IgG secondary
View all literature mentionsThis polyclonal targets LC3A/B antibody
View all literature mentionsThis monoclonal targets Bax
View all literature mentionsThis polyclonal targets RPS6KB1
View all literature mentionsThis polyclonal targets Beclin 1 antibody
View all literature mentionsThis polyclonal targets Bcl2
View all literature mentionsThis monoclonal targets GAPDH antibody [6C5]
View all literature mentionsThis polyclonal targets LAMP1
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