Anticancer effect of metformin against 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine-induced rat mammary carcinogenesis is through AMPK pathway and modulation of oxidative stress markers

Abstract

Objectives: Metformin, the type 2 anti-diabetes medication, showed antitumor activity both in vivo and in vitro. This study was carried out to investigate the mechanisms behind the metformin anticancer effect against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary carcinogenesis in female Sprague-Dawley rats. Methods: Rats received 10 doses of PhIP (75 mg/kg, p.o., days 1–5 and 8–12). Then, rats were treated with metformin for 26 weeks at a dose of 2 mg/ml in drinking water. Key findings: Metformin antitumor effect was mediated by increasing the adenosine monophosphate protein kinase (AMPK) activity, liver kinase B1, and decreasing the aromatase and insulin levels compared with the PhIP-administered group. Also, this treatment resulted in a significant decrease in mammary tissue oxidative stress markers and serum lipid profile. In parallel, mammary gland tumors found in PhIP+metformin group were all histologically benign included only (hyperplasia). However, most of the mammary gland tumors found in PhIP group were histologically malignant. Conclusions: These results showed that metformin antitumor effect was mediated through AMPK pathway, reducing oxidative stress and serum lipid levels. This study supports the potential benefit of using metformin as adjuvant therapy during breast cancer treatment.