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

Context: Metformin displays both direct and indirect anti-tumor effects. CXCL8 is a crucial down-stream 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. Conclusion: 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.