title: Metformin reverts the secretion of CXCL8 induced by TNF-α in primary cultures of human thyroid cells: an additional indirect anti-tumor effect of the drug.
abstract: BACKGROUND
  Metformin displays both direct and indirect anti-tumor effects. CXCL8 is a crucial downstream mediator of Nuclear-Factor-κB signaling related to the growth and progression of thyroid cancers. Targeting CXCL8 results in prolonged survival and reduced metastatic spread in in-vivo animal models of thyroid tumors.
  
  
  OBJECTIVE
  This study aimed to evaluate whether metformin inhibits the secretion of CXCL8 induced by Tumor-Necrosis-Factor-α (TNF-α) in primary cultures of normal and tumor human thyroid cells as well as in thyroid cancer cell lines.
  
  
  METHODS
  Normal human thyrocytes, papillary thyroid cancer cells, and thyroid cancer cell lines (TPC-1 and BCPAP) were stimulated with TNF-α (10 ng/mL) alone or in combination with metformin (0.01, 0.1, 1, 2.5, 5, and 10mM). CXCL8 levels were measured in the cell supernatants after 24 hours.
  
  
  RESULTS
  Metformin significantly and dose-dependently inhibited the TNF-α-induced CXCL8 secretion in both normal thyrocytes (ANOVA: F = 42.04; P < .0001) and papillary thyroid cancer cells (ANOVA: F = 21.691; P < .0001) but not in TPC-1 and BCPAP cell lines.
  
  
  CONCLUSIONS
  Metformin inhibits the TNF-α-induced CXCL8 secretion in primary cultures of normal thyroid cells and differentiated thyroid cancer cells at least of the most frequent poorly aggressive phenotype. The recruitment of neutrophils within the thyroid gland is a crucial metastasis-promoting factor, and it depends on the amount of CXCL8 produced by both tumor cells and by the more abundant normal thyroid cells exposed to TNF-α. Thus, the here-reported inhibiting effect of metformin on TNF-α-induced CXCL8 secretion could be considered as a further indirect anticancer property of the drug.
authors.affiliation: Unit of Internal Medicine and Endocrinology, Laboratory for Endocrine Disruptors (M.R., F.C., F.M., L.C.), and Allergy and Immunology Unit (P.P.), Fondazione Salvatore Maugeri I.R.C.C.S., 27100 Pavia, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Rotondi
authors.forename: Francesca
authors.initials: F
authors.lastname: Coperchini
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pignatti
authors.forename: Flavia
authors.initials: F
authors.lastname: Magri
authors.forename: Luca
authors.initials: L
authors.lastname: Chiovato
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002291:Carcinoma, Papillary; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D061251:Primary Cell Culture; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C508606:CXCL8 protein, human; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D008687:Metformin