Abstract
The purpose of this study was to investigate the effect of metformin on the responses of hepatocellular carcinoma (HCC) cells to γ-rays (low-linear energy transfer (LET) radiation) and carbon-ion beams (high-LET radiation). HCC cells were pretreated with metformin and exposed to a single dose of γ-rays or carbon ion beams. Metformin treatment increased radiation-induced clonogenic cell death, DNA damage, and apoptosis. Carbon ion beams combined with metformin were more effective than carbon ion beams or γ-rays alone at inducing subG1 and decreasing G2/M arrest, reducing the expression of vimentin, enhancing phospho-AMPK expression, and suppressing phospho-mTOR and phospho-Akt. Thus, metformin effectively enhanced the therapeutic effect of radiation with a wide range of LET, in particular carbon ion beams and it may be useful for increasing the clinical efficacy of carbon ion beams.
Keywords:
DNA damage; carbon ion beam; hepatocellular carcinoma cell; metformin; radiosensitivity.
MeSH terms
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AMP-Activated Protein Kinases / metabolism
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Apoptosis / drug effects
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Apoptosis / radiation effects
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Carcinoma, Hepatocellular / radiotherapy*
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DNA Damage
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Dose-Response Relationship, Radiation
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G2 Phase Cell Cycle Checkpoints / drug effects
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G2 Phase Cell Cycle Checkpoints / radiation effects
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Gamma Rays*
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Heavy Ion Radiotherapy*
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Hep G2 Cells
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Humans
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Liver Neoplasms / radiotherapy*
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Metformin / pharmacology*
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Radiation Tolerance / drug effects*
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Radiation-Sensitizing Agents / pharmacology*
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Signal Transduction / drug effects
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Signal Transduction / radiation effects
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TOR Serine-Threonine Kinases / metabolism
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Time Factors
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Vimentin / metabolism
Substances
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Radiation-Sensitizing Agents
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Vimentin
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Metformin
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MTOR protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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AMP-Activated Protein Kinases