Taxifolin Protects Against 5-Fluorouracil-Induced Cardiotoxicity in Mice Through Mitigating Oxidative Stress,...

Although 5-fluorouracil (5-FU) is widely utilized in cancer treatment, its side effects, including cardiotoxicity, limit its use. Taxifolin (TAX) is a bioactive anti-inflammatory and antioxidant flavonoid. This study aimed to elucidate the protective effect of TAX against 5-FU-induced cardiac injury in male mice. Mice were treated with TAX (25 and 50 mg/kg, orally) for 10 days and a single dose of 150 mg/kg 5-FU at day 8. Mice intoxicated with 5-FU showed increased creatine kinase-MB and lactate dehydrogenase activities and troponin I levels, with multiple cardiac histopathological changes. They also showed a significant increase in cardiac malondialdehyde (MDA) and nitric oxide (NO) and decreases in myocardial reduced glutathione (GSH) content and superoxide dismutase (SOD) and catalase (CAT) activities (P < 0.001). Pretreatment of 5-FU-injected mice with TAX suppressed cardiac injury, decreased MDA and NO contents (P < 0.001), and boosted antioxidant defenses in the myocardium. Moreover, TAX attenuated cardiac inflammatory response, as evidenced by the decreased expression levels of cardiac NF-κB p65, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines (P < 0.001). Largely, TAX ameliorated the decrease in Bcl-2 expression and the increase in BAX and caspase-3 in the heart. It also restored the cardiac Sirt1/Nrf2/HO-1 signaling pathway. In conclusion, TAX showed significant cardioprotective effects on 5-FU-induced cardiac injury and might represent a promising adjuvant in preventing cardiac injury associated with oxidative stress and inflammation.