title: Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents.
abstract: BACKGROUND
  Hyperinsulinemia and insulin resistance are the major reasons for a higher prevalence of several cancer entities in type 2 diabetes mellitus and obesity. Metformin exerts a growth-inhibitory effect by reducing hyperinsulinemia and by a direct cellular action.
  
  
  OBJECTIVE
  We investigated the effect of metformin on growth of differentiated human thyroid cells, anaplastic thyroid carcinoma cells, a doxorubicin-resistant thyroid carcinoma cell line, and thyroid cancer stem cells.
  
  
  METHODS
  The antimitogenic effect of metformin was studied in thyroid cells derived from goiters and in thyroid carcinoma cell lines by analysis of cell growth, cell cycle progression, and apoptosis. Furthermore, the influence of pretreatment with insulin or with chemotherapeutic agents on metformin-induced growth inhibition was investigated in thyroid carcinoma cells, in a doxorubicin-resistant thyroid carcinoma cell line, and in derived carcinoma stem cells.
  
  
  RESULTS
  Metformin showed an antimitogenic effect by inhibition of cell cycle progression and induction of apoptosis. In addition, metformin antagonized the growth-stimulatory effect of insulin, inhibited clonal cell growth, reduced thyroid cancer sphere formation, and potentiated the antimitogenic effect of chemotherapeutic agents such as doxorubicin and cisplatin on undifferentiated thyroid carcinoma cells. Remarkably, the antiproliferative effect of metformin was even found in a doxorubicin-resistant thyroid carcinoma cell line. The growth-inhibitory effect of metformin was, however, not restricted to differentiated thyroid cells and undifferentiated thyroid carcinoma cells but was also demonstrated in thyroid carcinoma cancer stem cells.
  
  
  CONCLUSIONS
  Metformin markedly diminished growth stimulation by insulin and showed an additive antimitogenic effect to chemotherapeutics agents. Therefore, our results suggest this drug as adjuvant treatment for thyroid cancer in type 2 diabetic patients.
authors.affiliation: Department of Medicine, St. Hedwig Hospital, Grosse Hamburger Strasse 5-11, D-10115 Berlin, Germany. m.derwahl@alexius.de.
authors.forename: Guofang
authors.initials: G
authors.lastname: Chen
authors.forename: Shuhang
authors.initials: S
authors.lastname: Xu
authors.forename: Kostja
authors.initials: K
authors.lastname: Renko
authors.forename: Michael
authors.initials: M
authors.lastname: Derwahl
mesh_terms: D018263:Adenocarcinoma, Follicular; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006044:Goiter, Nodular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007329:Insulin Antagonists / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D007329:Insulin Antagonists; D008687:Metformin