title: Metformin targets ovarian cancer stem cells in vitro and in vivo.
abstract: OBJECTIVE
  Studies in non-gynecologic tumors indicate that metformin inhibits growth of cancer stem cells (CSC). Diabetic patients with ovarian cancer who are taking metformin have better outcomes than those not taking metformin. The purpose of this study was to directly address the impact of metformin on ovarian CSC.
  
  
  METHODS
  The impact of metformin on ovarian cancer cell line growth and viability was assessed with trypan blue staining. Aldehyde dehydrogenase (ALDH) expressing CSC were quantified using FACS®. Tumor sphere assays were performed to determine the impact of metformin on cell line and primary human ovarian tumor CSC growth in vitro. In vivo therapeutic efficacy and the anti-CSC effects of metformin were confirmed using both tumor cell lines and ALDH(+) CSC tumor xenografts.
  
  
  RESULTS
  Metformin significantly restricted the growth of ovarian cancer cell lines in vitro. This effect was additive with cisplatin. FACS analysis confirmed that metformin reduced ALDH(+) ovarian CSC. Consistent with this, metformin also inhibited the formation of CSC tumor spheres from both cell lines and patient tumors. In vivo, metformin significantly increased the ability of cisplatin to restrict whole tumor cell line xenografts. In addition, metformin significantly restricted the growth of ALDH(+) CSC xenografts. This was associated with a decrease in ALDH(+) CSC, cellular proliferation, and angiogenesis.
  
  
  CONCLUSIONS
  Metformin can restrict the growth and proliferation of ovarian cancer stem cells in vitro and in vivo. This was true in cell lines and in primary human CSC isolates. These results provide a rationale for using metformin to treat ovarian cancer patients.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Shank
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Jacob
authors.initials: J
authors.lastname: Ghannam
authors.forename: Lourdes
authors.initials: L
authors.lastname: Cabrera
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Johnston
authors.forename: R Kevin
authors.initials: RK
authors.lastname: Reynolds
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Buckanovich
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004334:Drug Administration Schedule; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007004:Hypoglycemic Agents; D008687:Metformin; D000444:Aldehyde Dehydrogenase