Laboratorium voor experimentele geneeskunde en endocrinologie (LEGENDO), Faculty of Medicine, Catholic University Leuven, Leuven, Belgium.
J Steroid Biochem Mol Biol. 2011 Mar;124(1-2):1-9. doi: 10.1016/j.jsbmb.2010.12.008. Epub 2010 Dec 21.
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.
间变性甲状腺癌是最具侵袭性的癌症之一。活性形式的维生素 D，1,25-二羟维生素 D（3）（1,25(OH)(2)D(3)），已被证明在多种恶性肿瘤中具有抗增殖和/或再分化特性，包括甲状腺癌。本研究的目的是研究 1,25(OH)(2)D(3)和超级激动剂类似物 CD578 对间变性甲状腺癌的单独或联合紫杉醇、紫杉烷和琥珀酰亚胺基羟肟酸（SAHA）的作用，SAHA 是一种具有分化型甲状腺癌治疗潜力的有效的组蛋白去乙酰化酶抑制剂。四种人甲状腺癌细胞系（FTC-133、C643、8505C 和 HTh74）用 1,25(OH)(2)D(3)或 CD578 单独或联合紫杉醇或 SAHA 处理。评估对细胞生长和分化的影响。在集落形成试验中观察到对生长抑制的明显影响，绝对细胞计数显示在用 1,25(OH)(2)D(3)（10(-6)M）处理 72 小时后，所有细胞系的细胞减少 24-36%，在最敏感的细胞系 HTh74 中 120 小时后抑制率达到 60%。用浓度低 1000 倍的类似物 CD578 处理也显示出类似的生长抑制作用。这种生长抑制是由增殖抑制作用引起的，进一步支持细胞周期 G(0)-G(1)期的细胞比例增加和转录因子 E2F1 mRNA 表达降低。1,25(OH)(2)D(3)或 CD578 与紫杉醇或 SAHA 的联合治疗对增殖抑制具有相加作用，在某些条件下具有协同作用。分化分析显示，在用 1,25(OH)(2)D(3)处理后，钠碘转运体和甲状腺球蛋白 mRNA 的表达仅略有增加，联合治疗后无附加作用。TSH 受体或甲状腺过氧化物酶 mRNA 的表达没有观察到。我们的体外研究结果表明，超级激动剂维生素 D 类似物 CD578 有望成为间变性甲状腺癌的辅助抗增殖治疗药物，特别是与紫杉醇或 SAHA 等其他药物联合使用时。
