title: Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway.
abstract: OBJECTIVE
  To examine the effects of combination therapy with metformin and paclitaxel in endometrial cancer cell lines.
  
  
  METHODS
  ECC-1 and Ishikawa endometrial cancer cell lines were used. Cell proliferation was assessed after exposure to paclitaxel and metformin. Cell cycle progression was assessed by flow cytometry. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the effect of metformin/paclitaxel on the mTOR pathway.
  
  
  RESULTS
  Paclitaxel inhibited proliferation in a dose-dependent manner in both cell lines with IC(50) values of 1-5nM and 5-10nM for Ishikawa and ECC-1 cells, respectively. Simultaneous exposure of cells to various doses of paclitaxel in combination with metformin (0.5mM) resulted in a significant synergistic anti-proliferative effect in both cell lines (Combination Index<1). Metformin induced G1 arrest in both cell lines. Paclitaxel alone or in combination with metformin resulted in predominantly G2 arrest. Metformin decreased hTERT mRNA expression while paclitaxel alone had no effect on telomerase activity. Metformin stimulated AMPK phosphorylation and decreased phosphorylation of the S6 protein. In contrast, paclitaxel inhibited AMPK phosphorylation in the ECC-1 cell line and induced phosphorylation of S6 in both cell lines. Treatment with metformin and paclitaxel resulted in decreased phosphorylation of S6 in both cell lines but only had an additive effect on AMPK phosphorylation in the ECC-1 cell line.
  
  
  CONCLUSIONS
  Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. This combination may be a promising targeted therapy for endometrial cancer.
authors.affiliation: University of North Carolina, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Chapel Hill, NC, USA.
authors.forename: Rabbie K
authors.initials: RK
authors.lastname: Hanna
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Zhou
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Malloy
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhong
authors.forename: Paola A
authors.initials: PA
authors.lastname: Gehrig
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bae-Jump
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C509186:TERT protein, human; D019098:Telomerase; D017239:Paclitaxel