Anaplastic thyroid cancer represents one of the most aggressive
cancers. The active form of
vitamin D,
1,25-dihydroxyvitamin D(3) (
1,25(OH)(2)D(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)(2)D(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)(2)D(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 72h treatment with
1,25(OH)(2)D(3) (10(-6)M) and a 60% inhibition after 120h 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)(2)D(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)(2)D(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.