title: Altered expression of a metformin-mediated radiation response in SA-NH and FSa tumor cells treated under in vitro and in vivo growth conditions.
abstract: To assess the radiosensitizing effect of the biguanide drug metformin used alone or in combination with reactive oxygen species (ROS) modifying agents N-acetyl-L-cysteine (NAC) or emodin, and contrasted to the mitochondrial complex 1 inhibitor rotenone in altering the radiation responses of the p53 wild-type SA-NH and p53 mutant FSa mouse tumor lines grown either in vitro or in vivo.
  
  
  
  Tumor cells were grown to confluence in vitro and exposed to a single 4 Gy dose in the presence or absence of metformin (5 mM) and ROS modifiers or to 10 Gy with or without metformin as tumors in the flanks of C3H mice using a tumor growth delay assay.
  
  
  
  Both metformin and rotenone protected SA-NH (p < .001) while sensitizing FSa (p < .001) to 4 Gy. Neither NAC nor emodin altered metformin's action. Metformin was also directly toxic to FSa cells (p = .002). In contrast, in vivo metformin (250 mg/kg) sensitized both SA-NH (9-day growth delay, p < .05) and FSa (4-day growth delay, p < .05) tumors if administered 1 h before irradiation.
  
  
  
  Metformin effects on tumor cells measured under in vitro conditions may differ from those determined in vivo due to p53 and heterogeneous environmental factors.
authors.affiliation: a Department of Radiation and Cellular Oncology , The University of Chicago , Chicago , IL , USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Murley
authors.affiliation: a Department of Radiation and Cellular Oncology , The University of Chicago , Chicago , IL , USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Miller
authors.affiliation: a Department of Radiation and Cellular Oncology , The University of Chicago , Chicago , IL , USA.
authors.forename: Raziye Rana
authors.initials: RR
authors.lastname: Senlik
authors.affiliation: b Department of Preventive Medicine , Northwestern University, Feinberg School of Medicine , Chicago , IL , USA.
authors.forename: Alfred W
authors.initials: AW
authors.lastname: Rademaker
authors.affiliation: a Department of Radiation and Cellular Oncology , The University of Chicago , Chicago , IL , USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Grdina
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000528:radiation effects*; D004305:Dose-Response Relationship, Drug; D004642:Emodin / Q000008:administration & dosage; D005260:Female; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D008687:Metformin; D004642:Emodin; D000111:Acetylcysteine
keywords: Metformin; N-acetyl-l-cysteine; emodin; p53; rotenone