Re-evaluation of the anticarcinogenic effect of metformin in a chemically-induced hepatocellular carcinoma model not associated with diabetes

Abstract

Hepatocellular carcinoma (HCC) is the fourth cause of cancer mortality worldwide. Metformin is an antidiabetic drug that showed a prophylactic effect in the early stages of some cancers. This study aimed to reevaluate the anticarcinogenic effect of metformin in a cancer model not associated with diabetes. Also, to evaluate the effect of pharmacological antidiabetic dose of metformin (used in cancer studies) at the early stages of HCC versus the sub-pharmacological dose. HCC was induced by a single i.p injection of diethylnitrosamine followed by 16 biweekly i.p injections of carbon-tetrachloride. Metformin was i.p injected (25 or 250 mg/kg) post HCC induction for four weeks. The low dose of metformin suppressed HCC by reducing liver biomarkers levels, and the number and size of hepatic nodules. Also, metformin (25 mg/kg) downstaged HCC via activating Bax and suppressing Bcl-2, VEGF, and PCNA. Mice treated with metformin (250 mg/kg) exhibited lactic acidosis, death, and insignificant differences in nodules’ number and size and immunohistochemical markers compared to the HCC group. This study concluded that the pharmacological dose of metformin cannot be used at advanced stages of HCC, while the sub-pharmacological dose of metformin showed a promising anticarcinogenic effect in chemically-induced HCC model not associated with diabetes.