Journal
ONCOLOGY REPORTS
Volume 28, Issue 4, Pages 1406-1412Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/or.2012.1932
Keywords
metformin; ionizing radiation; hepatocellular carcinoma; adenosine triphosphate; DNA repair
Categories
Funding
- Department of Health of Guangdong Province [A2011290]
- Star of Science and Technology of Guangzhou [2012J2200032]
- Health Bureau of Guangzhou [20121A011163]
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Metformin, one of the most widely used antidiabetic drugs, has recently been associated with potential antitumorigenic effects. In this study, we evaluated the possible cytotoxic impact of combined low doses of metformin and ionizing radiation (IR) on 2 human hepatoma cell lines. The cytotoxic effect of metformin combined with IR was subsequently determined by clonogenic survival and cell cycle assays, assessment of mitochondrial complex I and lactate dehydrogenase (LDH) activity, measurement of cellular adenosine triphosphate (ATP) levels, comet assay and analyses of the formation and disappearance of phosphorylated histone H2AX (gamma-H2AX) protein. The combination of metformin and IR caused a much stronger cytotoxicity than the treatment with metformin or IR alone, leading to an similar to 80% decrease in cell viability and similar to 35% increase in the accumulation of cells in the G(2)/M phase of the cell cycle in the 2 hepatoma cell lines. In addition, a reduction in mitochondria! complex I activity (similar to 70%) and a significant increase in LDH activity, as well as lactate production were observed in the cells exposed to metformin. Interestingly, a severe depletion in ATP, increased olive tail moment and the delayed disappearance of gamma-H2AX expression were detected in the hepatoma cells treated by metformin plus IR. These findings show that the combination of a low concentration of metformin and IR results in the considerable enhancement of cytotoxic effects in human hepatoma cell lines, leading to decreased DNA repair by reducing ATP production. The data provided in this study may elucidate the remarkable efficiency of this combination treatment and suggest that metformin may be used as a potential adjunct to the radiotherapy of hepatocellular carcinoma.
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