Metformin ameliorated methotrexate-induced hepatorenal toxicity in rats in addition to its antitumor activity: two birds with one stone.

Methotrexate (MTX) is a drug used in treatment of various malignancies. Unfortunately, it leads to life-threatening complications including hepatorenal toxicity. Previous studies revealed the protective effects of metformin (MET) on hepatorenal toxicity in other models in addition to its anticancer effects. The current study investigates the effect of MET on MTX-induced hepatorenal toxicity and the possible mechanisms involved in this toxicity which can be overwhelmed by MET. Thirty male rats were divided into 3 groups: normal control, MTX treated and MET/MTX treated. After 7 days, MTX induced hepatorenal toxicity as proved by histological examinations and biochemical analysis of liver and kidney functions. Also, it led to significant increase in hepatic and renal malondialdehyde levels, significant decrease in hepatic and renal total antioxidant capacity levels and Na+/K+-ATPase activities and significant up regulation of mRNA expressions of nuclear factor kappa-light-chain-enhancer of activated B cells, cyclooxygenase-2 and caspase 3 compared with the control group. While, MET could significantly reduce hepatorenal toxicity and counteract the effects of MTX on all measured parameters. In conclusion, MET can be an effective adjuvant to MTX chemotherapy that could ameliorate its hepatorenal toxicity through antioxidant, anti-inflammatory and anti-apoptotic mechanisms.