The antidiabetic drug pioglitazone ameliorates betel-nut-induced carcinogenesis in mice by restoring normal lipid metabolism, reducing oxidative stress, and inducing apoptosis

Abstract

ABSTRACT Context: Oral administration (2 mg mL-1) of aqueous extract of betel nut (AEBN) for 24 weeks induced oncogenic alterations in the liver of female Swiss Albino mice concomitant with aberrant lipid metabolism, overactivation of Akt/mTOR signaling, and loss of apoptosis. Aim: This study was designed to investigate the potential of repurposing the antidiabetic drug pioglitazone for alleviating AEBN-induced carcinogenesis. Methods: Sera of animals were evaluated for lipid profile and free fatty acid levels. Liver tissues were investigated for oxidative stress, histopathology, and expression of proteins involved in lipid metabolism and oncogenesis by western blotting. Apoptosis was determined using TUNEL assay. Results: Coadministration of pioglitazone (10 mg kg-1 b.w) with AEBN for 8 weeks restored normal lipid profile and AMPK/ACC signaling, reduced FASN and HMGCR expressions and oxidative stress, and actively induced Akt/mTOR-mediated apoptosis in the liver. Conclusions: Pioglitazone can effectively alleviate AEBN-induced carcinogenesis in mice.