title: Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial.
abstract: BACKGROUND
  Metformin, an antidiabetic drug, decreases the incidence of various cancers in diabetic patients. Metformin-induced inhibition of cancer cell proliferation has been confirmed in vitro but not in humans. Because endometrial cancer is associated with insulin resistance, the authors investigated whether a diabetes-therapeutic metformin dose inhibits cancer cell growth in patients with endometrial cancer.
  
  
  METHODS
  A dose of metaformin was administered (1500-2250 mg/day) to 31 patients with endometrial cancer preoperatively for 4 to 6 weeks. Cell proliferation was assessed in patient tissues using immunohistochemical and Western blot analyses and DNA synthesis was measured in serum using a thymidine uptake assay. All statistical tests were 2-sided. P values of < .05 were considered statistically significant.
  
  
  RESULTS
  Preoperative metformin treatment decreased DNA synthesis in sera and significantly reduced the Ki-67 (mean proportional decrease, 44.2%; 95% confidence interval [95% CI], 35.4-53.0 [P < .001]) and topoisomerase IIα (mean proportional decrease, 36.4%; 95% CI, 26.7-46.0 [P < .001]) labeling indices. Levels of phospho-ribosomal protein S6 and phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) were found to be significantly decreased and phospho-adenosine monophosphate-activated protein kinase and p27 levels were significantly increased. Preoperative metformin use caused significant decreases in circulating factors, including insulin, glucose, insulin-like growth factor 1, and leptin. DNA synthesis-stimulating activity in patient sera was significantly decreased during metformin administration.
  
  
  CONCLUSIONS
  An antidiabetic dose of metformin inhibited endometrial cancer cell growth in vivo, an effect likely due to its effect on humoral factor(s). This translational study provides considerable rationale to initiate large clinical trials.
authors.affiliation: Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Mitsuhashi
authors.forename: Takako
authors.initials: T
authors.lastname: Kiyokawa
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Makio
authors.initials: M
authors.lastname: Shozu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020360:Neoadjuvant Therapy / Q000379:methods*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011446:Prospective Studies; D038601:Ribosomal Protein S6 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D038601:Ribosomal Protein S6; C413374:p27 antigen; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D055372:AMP-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D004250:DNA Topoisomerases, Type II
keywords: endometrial cancer; growth inhibition; in vivo; insulin resistance; metformin