title: Metformin Radiosensitizes p53-Deficient Colorectal Cancer Cells through Induction of G2/M Arrest and Inhibition of DNA Repair Proteins.
abstract: The present study addressed whether the combination of metformin and ionizing radiation (IR) would show enhanced antitumor effects in radioresistant p53-deficient colorectal cancer cells, focusing on repair pathways for IR-induced DNA damage. Metformin caused a higher reduction in clonogenic survival as well as greater radiosensitization and inhibition of tumor growth of p53-/- than of p53+/+ colorectal cancer cells and xenografts. Metformin combined with IR induced accumulation of tumor cells in the G2/M phase and delayed the repair of IR-induced DNA damage. In addition, this combination significantly decreased levels of p53-related homologous recombination (HR) repair compared with IR alone, especially in p53-/- colorectal cancer cells and tumors. In conclusion, metformin enhanced radiosensitivity by inducing G2/M arrest and reducing the expression of DNA repair proteins even in radioresistant HCT116 p53-/- colorectal cancer cells and tumors. Our study provides a scientific rationale for the clinical use of metformin as a radiosensitizer in patients with p53-deficient colorectal tumors, which are often resistant to radiotherapy.
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.|Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
authors.forename: Youn Kyoung
authors.initials: YK
authors.lastname: Jeong
authors.affiliation: Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Division of Heavy Ion Clinical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
authors.forename: Eun Ho
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.
authors.forename: Hunjoo
authors.initials: H
authors.lastname: Ha
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008687:Metformin / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D011838:Radiation-Sensitizing Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008687:Metformin