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Metformin, one of the most widely used antidiabetic drugs, has recentlybeen associated with potential antitumorigenic effects. In this study, we evaluatedthe possible cytotoxic impact of combined low doses of metformin and ionizingradiation (IR) on 2 human hepatoma cell lines. The cytotoxic effect of metformincombined with IR was subsequently determined by clonogenic survival and cell cycleassays, assessment of mitochondrial complex I and lactate dehydrogenase (LDH)activity, measurement of cellular adenosine triphosphate (ATP) levels, comet assayand analyses of the formation and disappearance of phosphorylated histone H2AX(γ-H2AX) protein. The combination of metformin and IR caused a much stronger cytotoxicitythan the treatment with metformin or IR alone, leading to an ~80% decrease incell viability and ~35% increase in the accumulation of cells in the G2/M phaseof the cell cycle in the 2 hepatoma cell lines. In addition, a reduction in mitochondrialcomplex I activity (~70%) and a significant increase in LDH activity, as wellas lactate production were observed in the cells exposed to metformin. Interestingly,a severe depletion in ATP, increased olive tail moment and the delayed disappearanceof γ-H2AX expression were detected in the hepatoma cells treated by metforminplus IR. These findings show that the combination of a low concentration of metforminand IR results in the considerable enhancement of cytotoxic effects in human hepatomacell lines, leading to decreased DNA repair by reducing ATP production. The dataprovided in this study may elucidate the remarkable efficiency of this combinationtreatment and suggest that metformin may be used as a potential adjunct to theradiotherapy of hepatocellular carcinoma.

oncology reports

Enhanced cytotoxic effect of low doses of metformin combined with ionizing radiation on hepatoma cells via ATP deprivation and inhibition of DNA repair