Osthole attenuates trastuzumab-induced cardiotoxicity in mice by enhancing autophagy via regulating the p38MAPK/mTOR signaling pathway

Background and aim Trastuzumab (TRZ)-induced cardiotoxicity impairs breast cancer patients' quality of life, with no effective prevention currently. Osthole (OST) has been reported to exert cardioprotective effects in certain cardiovascular diseases. The purpose of this study was to investigate the probable mechanisms behind the protective effect of OST against TRZ-induced cardiotoxicity. Experimental procedure Mice were pretreated with OST (50 or 100 mg/kg) for 5 days, followed by TRZ (10 mg/kg, 10 days) to establish a cardiotoxicity model. The protective effects of OST on TRZ-induced cardiotoxicity was assessed via echocardiography, cardiac weight index (CWI), serum myocardial injury markers, H&E, and Masson staining. To explore the mechanisms, SOD/MDA levels, DHE staining (ROS), Nick-End-Labeling (TUNEL) staining (apoptosis), and Western blot were performed with/without 3-methyladenine (autophagy inhibitor) or SB203580 (p38MAPK inhibitor). Results and Conclusion OST pretreatment significantly improved cardiac function, alleviated myocardial damage and fibrosis, and enhanced autophagy (increased LC3II/I, Beclin-1 and decreased p62). Oxidative stress damage was ameliorated by OST, as demonstrated by higher activity of SOD, lower level of MDA and reactive oxygen species (ROS). In addition, OST decreased the ratio of Bax/Bcl-2 and Caspase-3 expression, and reduced apoptosis rate. OST activated p38MAPK (increased p-p38MAPK level) while inhibiting mTOR (decreased p-mTOR level). While these effects were blocked by the autophagy inhibitor 3-MA or p38MAPK inhibitor SB203580. These results indicated that OST has a protective effect on TRZ-induced cardiotoxicity, and its underlying mechanism may be related to enhancing autophagy via the p38MAPK/mTOR signaling pathway, thus reducing oxidative stress and apoptosis.