1,25-Dihydroxyvitamin D₃ and a superagonistic analog in combination with paclitaxel or suberoylanilide hydroxamic acid have potent antiproliferative effects on anaplastic thyroid cancer

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• 作者：Isabelle Clinckspoor^a ; ^{isabelle.clinckspoor@med.kuleuven.be} ; Lieve Verlinden^a ; ^{lieve.verlinden@med.kuleuven.be} ; Lutgart Overbergh^a ; ^{lutgart.overbergh@med.kuleuven.be} ; Christopher Korch^b ; ^{christopher.korch@ucdenver.edu} ; Roger Bouillon^a ; ^{roger.bouillon@med.kuleuven.be} ; Chantal Mathieu^a ; ^{chantal.mathieu@med.kuleuven.be} ; Annemieke Verstuyf^a ; ^{mieke.verstuyf@med.kuleuven.be} ; Brigitte Decallonne^a ; ^{brigitte.decallonne@med.kuleuven.be}
• 关键词：Thyroid ; Cancer ; Vitamin D ; Nonsteroidal analog ; SAHA ; Paclitaxel
• 刊名：The Journal of Steroid Biochemistry and Molecular Biology
• 出版年：2011
• 出版时间：March 2011
• 年：2011
• 卷：124
• 期：1-2
• 页码：1-9
• 全文大小：967 K

文摘

Anaplastic thyroid cancer represents one of the most aggressive cancers. The active form of vitamin D, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), 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)₂D₃ 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)₂D₃ 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)₂D₃ (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 G₀–G₁ phase of the cell cycle and by a decreased transcription factor E2F1 mRNA expression. Combination treatments of 1,25(OH)₂D₃ 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)₂D₃, 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.