Tangeretin, An Active Flavonoid in Citrus Peel, Alleviates Cisplatin-Induced Cardiotoxicity via the Activation of AMPK and the Prevention on Mitochondrial Dysfunction

Abstract

Cardiotoxicity is a major side effects of cisplatin use in cancer therapy and often delays optimal cancer management. Tangeretin (TG), a natural polymethoxyflavone found in citrus peels, exhibits significant biological activity against myocardial injury. In this study, we initially explored the protective effect of TG on cisplatin-induced cardiotoxicity in vitro and in vivo. TG (1.25, 2.5, and 5 µM) protected against cisplatin-induced (40 µM) injury in H9c2 cells, increased the quantity of mitochondria, enhanced membrane protein expressions of glucose transporters (GLUT 4), and stabilized the mitochondrial membrane potential. Concurrently, cisplatin-induced cardiotoxicity in vivo was significantly mitigated by TG (50 and 100 mg/kg for 3 weeks).This was evidenced by the reduction of cardiac function indices (creatine kinase, isoenzymes MB, troponin T, and lactate dehydrogenase), cardiac morphological changes, and the suppression of heart injury-associated proteins. Furthermore, TG treatment significantly increased the activation of AMP-activated protein kinase (AMPK), reduced the inactivation of ACC protein, and decreased the expression of phosphorylated p38 MAPK protein, which inhibited the opening of myocardial mitochondrial permeability transition pore and cell apoptosis. In conclusion, our work provides insight into the underlying molecular mechanisms through which TG modulates AMPK signaling pathways and mitochondrial dysfunction, thus protecting the heart against cisplatin-mediated myocardial injury.