Febuxostat protects from Doxorubicin induced hepatotoxicity in rats via regulation of NF-κB p65/NLRP3 inflammasome and SIRT-1/AMPK pathways

Abstract

Doxorubicin (DOX) is a highly potent broad-spectrum anticancer drug, but it has severe side effects, including hepatotoxicity. Therefore, we evaluated the efficacy of febuxostat (FBX), a specific inhibitor of xanthine oxidase and antioxidant, in blocking hepatotoxicity associated with DOX in rats. Rats were treated with FBX (10 or 15 mg/kg/day orally for 2 weeks) and given DOX (15 mg/kg as single dose at the 7th day, intraperitoneal) to induce hepatotoxicity. The results indicated that FBX could reduce the pathological alterations of liver tissues induced by DOX and ameliorate the inappropriate changes in liver function biomarkers (AST, ALT, and ALP) in serum, oxidative stress parameters (catalase, superoxide dismutase, NOX1, NQO-1, HO-1, Keap-1, and Nrf2) and inflammatory markers in the liver (NF-κB p65, TNF-α, NLRP3). Additionally, FBX attenuated the p53, BAX, cytochrome C, caspase-9, and caspase-3 levels to restrain cell apoptosis. In addition, FBX therapy was found to increase protein levels of SIRT-1 and AMPK in the liver. These findings demonstrate that FBX can reduce the hepatotoxicity caused by DOX in rats through mechanisms that counteract oxidative stress, inflammation, and apoptosis.

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