title: Low and high linear energy transfer radiation sensitization of HCC cells by metformin.
abstract: The purpose of this study was to investigate the efficacy of metformin as a radiosensitizer for use in combination therapy for human hepatocellular carcinoma (HCC). Three human HCC cell lines (Huh7, HepG2, Hep3B) and a normal human hepatocyte cell line were treated with metformin alone or with radiation followed by metformin. In vitro tests were evaluated by clonogenic survival assay, FACS analysis, western blotting, immunofluorescence and comet assay. Metformin significantly enhanced radiation efficacy under high and low Linear Energy Transfer (LET) radiation conditions in vitro. In combination with radiation, metformin abrogated G2/M arrest and increased the cell population in the sub-G1 phase and the ROS level, ultimately increasing HCC cellular apoptosis. Metformin inhibits the repair of DNA damage caused by radiation. The radiosensitizing effects of metformin are much higher in neutron (high LET)-irradiated cell lines than in γ (low LET)-irradiated cell lines. Metformin only had a moderate effect in normal hepatocytes. Metformin enhances the radiosensitivity of HCC, suggesting it may have clinical utility in combination cancer treatment with high-LET radiation.
authors.affiliation: Division of Heavy Ion Clinical Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-Gu, Seoul 139-706, South Korea.
authors.forename: Eun Ho
authors.initials: EH
authors.lastname: Kim
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Kim
authors.forename: Chul-Koo
authors.initials: CK
authors.lastname: Cho
authors.forename: Won-Gyun
authors.initials: WG
authors.lastname: Jung
authors.forename: Youn Kyoung
authors.initials: YK
authors.lastname: Jeong
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Jeong
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000628:therapy*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004359:Drug Therapy, Combination; D006801:Humans; D018499:Linear Energy Transfer / Q000187:drug effects*; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D008687:Metformin / Q000008:administration & dosage*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D008687:Metformin
keywords: DNA damage; Metformin; hepatocarcinoma cells; high-LET radiation; radiosensitivity