title: The antitumor effect of metformin with and without carboplatin on primary endometrioid endometrial carcinoma in vivo.
abstract: OBJECTIVE
  New treatment options for advanced and recurrent endometrial carcinoma (EC) are necessary. Epidemiological studies showed that diabetic patients using metformin have reduced risks of endometrial cancer (EC) incidence. Moreover, pre- and clinical studies demonstrated an antitumor effect by metformin, with and without additional treatments, for different solid malignancies. However, cancer cell-autonomous effects of metformin on EC have not been fully characterized yet. The aim of this study was to investigate the effect of metformin, with or without carboplatin, on patient-derived primary endometrioid EC cells xenografted in nude mice, to assess its ability to reduce or impair growth in already established tumors.
  
  
  METHODS
  Two xenograft models were established by subcutaneous inoculation of primary endometrioid EC cell suspensions. Tumors were allowed to grow and then mice were treated with metformin (250 mg/kg, daily, p.o.), carboplatin (50 mg/kg, 1×/week, i.p.), or the combination of both compounds at the same concentration as single treatment, for three weeks. Effects of metformin treatment on the tumor mass were determined by tumor growth follow-up. Metformin influences on AMPK/mTOR cell signaling were evaluated by investigating AKT, AMPK and S6 phosphorylation levels.
  
  
  RESULTS
  In vivo, metformin did not affect the growth of EC tumors established from patient-derived primary cultures and the phosphorylation of AKT, AMPK and S6. In addition, no enhanced antitumor effect was determined by combining metformin and carboplatin treatments.
  
  
  CONCLUSIONS
  Metformin, at clinically relevant concentrations, did not show effects on the growth of already established tumors. Adding metformin to carboplatin did not have synergistic effects.
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: Stefanie.Schrauwen@med.kuleuven.be.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schrauwen
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: coenegrachtslieve@hotmail.com.
authors.forename: Lieve
authors.initials: L
authors.lastname: Coenegrachts
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: anna.cattaneo5@studenti.unimi.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Cattaneo
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: Els.Hermans@uzleuven.be.
authors.forename: Els
authors.initials: E
authors.lastname: Hermans
authors.affiliation: KU Leuven, Department of Oncology, Laboratory for Translational Genetics, B-3000 Leuven, Belgium; VIB, Vesalius Research Center (VRC), B-3000 Leuven, Belgium. Electronic address: Diether.Lambrechts@vib-kuleuven.be.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: Frederic.Amant@uzleuven.be.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Amant
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D016190:Carboplatin / Q000008:administration & dosage; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D008687:Metformin; D016190:Carboplatin
keywords: Endometrioid endometrial carcinoma; In vivo; Metformin; Primary cell cultures