title: Nimotuzumab enhances the radiosensitivity of cancer cells in vitro by inhibiting radiation-induced DNA damage repair.
abstract: BACKGROUND
  Nimotuzumab is a humanized IgG1 monoclonal antibody specifically targeting EGFR. In this study, we aimed to investigate the molecular mechanisms of nimotuzumab in its effects of enhancing cancer cell radiosensitivity.
  
  
  RESULTS
  Lung cancer A549 cells and breast cancer MCF-7 cells were pretreated with or without nimotuzumab for 24 h before radiation to perform the clonogenic survival assay and to analyze the cell apoptosis by flow ctyometry. γ-H2AX foci were detected by confocal microscopy to assess the effect of nimotuzumab on radiation induced DNA repair. EGFR activation was examined and the levels of DNA damage repair related proteins in A549 cells at different time point and at varying doses exposure after nimotuzumab and radiation treatment were examined by Western blot. Pretreatment with nimotuzumab reduced clonogenic survival after radiation, inhibited radiation-induced EGFR activation and increased the radiation-induced apoptosis in both A549 cells and MCF-7 cells. The foci of γ-H2AX 24 h after radiation significantly increased in nimotuzumab pretreated cells with different doses. The phosphorylation of AKT and DNA-PKcs were remarkably inhibited in the combination group at each dose point as well as time point.
  
  
  CONCLUSIONS
  Our results revealed that the possible mechanism of nimotuzumab enhancing the cancer radiosensitivity is that nimotuzumab inhibited the radiation-induced activation of DNA-PKcs through blocking the PI3K/AKT pathway, which ultimately affected the DNA DSBs repair.
authors: Department of Radiation Oncology, the Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors: Yuan-yuan
authors: YY
authors: Qu
authors: Song-liu
authors: SL
authors: Hu
authors: Xiang-ying
authors: XY
authors: Xu
authors: Rui-zhi
authors: RZ
authors: Wang
authors: Hong-yang
authors: HY
authors: Yu
authors: Jian-yu
authors: JY
authors: Xu
authors: Lin
authors: L
authors: Chen
authors: Guang-lu
authors: GL
authors: Dong
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D005720:Gamma Rays; D005786:Gene Expression Regulation; D006657:Histones / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D015398:Signal Transduction
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D051747:DNA-Activated Protein Kinase; D066246:ErbB Receptors; D006657:Histones; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C468783:H2AX protein, human; C501466:nimotuzumab; C512478:EGFR protein, human; C497263:PRKDC protein, human
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