Background: Metformin, a widely used anti-diabetic drug has gained enormous attention as an anticancer agent. This study seeks to investigate the efficacy of metformin in ameliorating aqueous extract of betel-nut (AEBN) and arecoline induced carcinogenesis in a murine model.
Methods: Swiss albino mice were exposed to AEBN (2 mg ml-1) and arecoline (10 μg ml-1) in drinking water for 16 weeks followed by co-administration of metformin (75 mg kg-1 or 150 mg kg-1) for 4 or 8 weeks. Histological changes and oxidative stress were assessed by haematoxylin and eosin staining, TBARS assay and protein carbonylation assay respectively. Lipid profile was determined using an automated analyzer. Expression of total and phosphorylated AMPK, ACC and p53 were determined by immunoblotting.
Results: AEBN and arecoline induced dyslipidemia by downregulating AMPK (Thr-172) and activating ACC (Ser-79); they also downregulated tumor suppressor p53 (Ser-15). Metformin treatment induced AMPK-dependent alleviation of dyslipidemia in a dose and time dependent manner, upregulated p53 (Ser-15), restored tissue architecture and reduced oxidative stress in tissues of AEBN and arecoline treated mice.
Conclusion: This study establishes that betel nut induces dyslipidemia through its alkaloid, arecoline by inhibition of AMPK (Thr-172) and activation of ACC (Ser-79) and highlights the therapeutic potential of metformin for treatment of betel-nut induced carcinogenesis, indicating the repurposing of the old drug in a new avenue.
Keywords: Arecoline; Betel-nut; Carcinogenesis; Lipid profile; Metformin.
Copyright © 2019 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.