Abstract
Anaplastic thyroid cancer represents one of the most aggressive cancers. The active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3), has been shown to have antiproliferative and/or redifferentiating properties in several malignancies, including thyroid cancer. The objective of this study was to investigate the effects of 1,25(OH) 2D 3 and the superagonistic analog CD578 in anaplastic thyroid cancer, alone or in combination with paclitaxel, a taxane, and suberoylanilide hydroxamic acid (SAHA), a potent histone deacetylase inhibitor with promising effects in undifferentiated thyroid cancer. Four human thyroid cancer cell lines (FTC-133, C643, 8505C and HTh74) were treated with 1,25(OH) 2D 3 or CD578, alone or in combination with paclitaxel or SAHA. Effects on cell growth and differentiation were evaluated. Clear effects on growth arrest were observed in a clonogenic assay, and absolute cell counts demonstrated a 24–36% reduction in all cell lines after 72 h treatment with 1,25(OH) 2D 3 (10 −6 M) and a 60% inhibition after 120 h in the most sensitive cell line HTh74. A similar growth inhibition was shown after treatment with a 1000-fold lower concentration of analog CD578. This growth arrest was explained by antiproliferative effects, further supported by an increased % of cells in the G 0–G 1 phase of the cell cycle and by a decreased transcription factor E2F1 mRNA expression. Combination treatments of 1,25(OH) 2D 3 or CD578 with paclitaxel or SAHA resulted in an additive and in some conditions a synergistic effect on the inhibition of proliferation. Redifferentiation analysis revealed only a modest increase in sodium iodide symporter and thyroglobulin mRNA expression after treatment with 1,25(OH) 2D 3, without additive effect after combination treatment. No effects were observed on TSH-receptor or thyroid peroxidase mRNA expression. Our in vitro findings demonstrate that the superagonistic vitamin D analog CD578 holds promise as adjuvant antiproliferative therapy of anaplastic thyroid cancer, especially in combination with other drugs such as paclitaxel or SAHA.
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