ABSTRACT
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 (2â¯mgâ¯ml-1) and arecoline (10⯵g ml-1) in drinking water for 16 weeks followed by co-administration of metformin (75â¯mgâ¯kg-1 or 150â¯mgâ¯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.
Subject(s)
Areca , Arecoline/adverse effects , Carcinogenesis/drug effects , Carcinogenesis/metabolism , Metformin/pharmacology , Plant Extracts/adverse effects , AMP-Activated Protein Kinases/metabolism , Animals , Disease Models, Animal , Dyslipidemias/drug therapy , Ectodermal Dysplasia , Female , Liver/drug effects , Liver/pathology , Lung/drug effects , Lung/pathology , Mice , Signal Transduction , Tumor Suppressor Protein p53/metabolismABSTRACT
Anti-diabetic drugs are an important group of therapeutics used worldwide. Different anti-diabetic drugs lower blood glucose level by different mechanisms. In recent years, numerous investigations have been performed based on both comparative and cohort studies, in order to establish the relationship between anti-diabetic pharmacotherapy and cancer incidence as well as mortality due to cancer. Some anti-diabetic drugs have been found to exhibit anti-cancer activity while others might increase the risk for cancer. The underlying cause for this disparity is likely to be the varying mechanisms of action of these drugs in controlling blood glucose level. This review discusses the various carcinogenic and/or anti-cancer effects of commonly used anti-diabetic drugs. The information is vital in view of the fact that diabetes mellitus is a commonly occurring disease with a rising incidence rate.
