Tanshinone IIA Restores Dynamic Balance of Autophagosome/Autolysosome in Doxorubicin-Induced Cardiotoxicity via Targeting Beclin1/LAMP1

Abstract

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.

Luteolin Attenuates Doxorubicin-Induced Cardiotoxicity Through Promoting Mitochondrial Autophagy

“…It remains debatable whether activating or inhibiting autophagy is beneficial for doxorubicin-induced cardiotoxicity (Sishi et al, 2013;Bartlett et al, 2017;Koleini and Kardami, 2017). It is conceived that low dose doxorubicin disrupts cardiac autophagy by inhibiting lysosomal biogenesis and function due to the abnormalities of TFEB function (Kawaguchi et al, 2012;Bartlett et al, 2016;Wang et al, 2019b). Disruption in cardiac autophagic processes leads to ROS overproduction, and ψm dissociation, contributing to mitochondria-mediated apoptosis and death, consistent with the previous finding (Bartlett et al, 2016).…”

TFEB-NF-κB inflammatory signaling axis: a novel therapeutic pathway of Dihydrotanshinone I in doxorubicin-induced cardiotoxicity

“…H9C2 cells in our study were obtained from China Infrastructure of Cell Line Resources. The establishment of DOX-stimulated H9C2 cell model has been mentioned in our previous study [26]. For pharmacological treatments, we set up various groups: Control group, DOX group (with DOX 1 μM), DOX + DHT group (with DHT 10 nM), DOX + DHT + MHY1485 group (with DHT 10 nM and MHY1485 5 μM) and DOX + PDTC group (with PDTC 100 nM).…”

“…Protein samples were prepared and detected according to our previously described methods [26]. The antibodies we used were listed in Table 2.…”

“…To further investigate the effects of DHT on NF-κB-mediated inflammation in myocardial cells, a DOX-stimulated H9C2 cell model was established [26]. Pre-treatment with 10~100 nM DHT for 24 h and co-treatment for 24 h proved to be effective ( Fig.…”

Anti-Tumor Drug-Loaded Oxygen Nanobubbles for the Degradation of HIF-1α and the Upregulation of Reactive Oxygen Species in Tumor Cells

“…The chemotherapeutic mechanism of Dox is based on the intercalation with DNA, inhibition of the critical DNA replicating enzyme topoisomerase II, and production of reactive oxygen species (ROS) [69,70,71,72]. Several side effects of free Dox have been reported, and are related to cardiac toxicity and cardiomyopathy [70,73,74]. Therefore, to reduce the side effects of Dox and improve the efficiency and effectiveness of Dox delivery, liposome-encapsulated Dox has been developed for commercial use [71,75].…”