title: Enhanced cytotoxic effect of low doses of metformin combined with ionizing             radiation on hepatoma cells via ATP deprivation and inhibition of DNA repair.
abstract: 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             (γ-H2AX) protein. The combination of metformin and IR caused a much stronger cytotoxicity             than the treatment with metformin or IR alone, leading to an ~80% decrease in             cell viability and ~35% increase in the accumulation of cells in the G2/M phase             of the cell cycle in the 2 hepatoma cell lines. In addition, a reduction in mitochondrial             complex I activity (~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 γ-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.
authors: Cancer Research Institute and Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510095, PR China.
authors: Jifang
authors: J
authors: Liu
authors: Min
authors: M
authors: Hou
authors: Taize
authors: T
authors: Yuan
authors: Gao
authors: G
authors: Yi
authors: Shuxu
authors: S
authors: Zhang
authors: Xunfan
authors: X
authors: Shao
authors: Jinhui
authors: J
authors: Chen
authors: Xiaoting
authors: X
authors: Jia
authors: Zhimin
authors: Z
authors: He
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D006836:Hydro-Lyases / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D008687:Metformin / Q000494:pharmacology*; D011839:Radiation, Ionizing
chemical_list: C468783:H2AX protein, human; D006657:Histones; D000255:Adenosine Triphosphate; D008687:Metformin; D006836:Hydro-Lyases; C045581:lactate dehydratase