Abstract
BackgroundExpression of IL-8 and its receptors CXCR1 and CXCR2 is a common occurrence in human epithelial thyroid cancer (TC). In human TC samples, IL-8 expression is associated with tumor progression. IL-8 enhances proliferation, survival, motility, and leads to the maintenance of stemness features and tumor-initiating ability of TC cells. Here, we studied the effects of Reparixin (formerly Repertaxin), a small molecular weight CXCR1 and CXCR2 inhibitor, on the malignant phenotype of various TC cell lines.ResultsReparixin impaired the viability of epithelial thyroid cancerous cells, but not that of the non-malignant counterpart. Reparixin treatment significantly decreased TC cell survival, proliferation, Epithelial-to-Mesenchymal Transition (EMT) and stemness. CXCR1 and CXCR2 silencing abolished these effects. Reparixin sensitized TC cells to Docetaxel and Doxorubicin in culture. Used as single agent, Reparixin significantly inhibited TC cell tumorigenicity in immunodeficient mice. Finally, Reparixin potentiated the effects of Docetaxel on TC cell xenotransplants in mice.Materials and MethodsWe assessed the effects of Reparixin on TC cell viability (by growth curves, BrdU incorporation, TUNEL assay), EMT (by RT-PCR, Flow Cytometry, Migration assays), stemness (by RT-PCR, Flow Cytometry, sphere-formation and self-renewal), and tumorigenicity (by xenotransplantation in nude mice).ConclusionsThe present study suggests that Reparixin, both alone and in combination with classic chemotherapics, represents a novel potential therapeutic strategy for aggressive forms of TC.
Highlights
Thyroid cancer (TC) is the most common endocrine malignancy
The present study suggests that Reparixin, both alone and in combination with classic chemotherapics, represents a novel potential therapeutic strategy for aggressive forms of thyroid cancer (TC)
In order to determine the effects of Reparixin on thyroid epithelial cells, we selected PC CL3 [16] and Nthy-ori-3.1 as representative of non-malignant thyroid cells [8]. 8505c, CAL62, and SW1736 cell lines were instead chosen as representative of undifferentiated and aggressive TC cells [8]
Summary
Thyroid cancer (TC) is the most common endocrine malignancy. Carcinomas deriving from thyroid follicular epithelial cells include follicular (FTC), papillary (PTC), poorly differentiated (PDTC) and anaplastic thyroid carcinomas (ATC) [1]. PDTC and ATC, instead, typically exhibit aggressive histologic features such as extrathyroidal extension, vascular invasion, and tumor necrosis [1]. They are refractory to radioiodine and chemotherapics [2]. Expression of IL-8 and its receptors CXCR1 and CXCR2 is a common occurrence in human epithelial thyroid cancer (TC). We studied the effects of Reparixin (formerly Repertaxin), a small molecular weight CXCR1 and CXCR2 inhibitor, on the malignant phenotype of various TC cell lines
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