Abstract:
Total thyroidectomy is the treatment of choice in differentiated thyroid carcinomas. Patients usually receive postoperative radioiodine treatment in an attempt to ablate the remaining thyroid tissue and metastases. However, the success of the 131I-Iodidtherapy depends on the ability of the thyroid cells to retain and utilize the iodine and therefore a functioning Na+-I- -Symporter is essential. The aim of the present study was to investigate the effects of several substances, which potentially induce re-differentiation, in the cultivated human follicular thyroid carcinoma cell line FTC-238. The 125I-Iodid-uptake served as a differentiation parameter. Cell proliferation was determined by measuring the 3H-Thymidine-uptake and NIS and Pendrin expression was determined by immunocytochemistry and Western Blots. Apoptosis was analyzed by FACS-Analysis.
The following substances were tested:
-Retinoids (all-trans-, 9-cis-, 13-cis-Retinoic Acid, all-trans- and 13-cis-Retinol): A statistically significant increased 125I-Iodid-uptake accompanied by an increased NIS and Pendrin expression was measured in the thyrocytes under the influence of 9-cis-, 13-cis Retinoid Acid and 13-cis-Retinol. 3H-Thymidine-uptake increased gradually under the influence of 13-cis-Retinoic Acid. All-trans-Retinol induced, after a increased thymidine incorporation in the beginning of the experiment, a statistically significant decrease of the proliferation rate. The rate of apoptosis was only minimally enhanced.
-DNA-Methyltransferase-Inhibitors: 5-Aza-2'-Deoxycytidine induces an increased 125I-Iodid-uptake by the malignant thyroid cells. Due to possible methodological problems, NIS and Pendrin expression is not increased. The 3H-Thymidine incorporation is significantly increased. In comparison to the control group, the rates of apoptosis under the influence of 5-Aza-2'-Deoxycytidine are not enhanced.
-Protein Kinase B-Inhibitors (AKT I-, AKT V- Inhibitor and AKT-Inhibitors + arsenic acid): Overall the 125I-Iodid- and 3H-Thymidine- uptake is decreased. However the reduced 125I-Iodid-Uptake does not correlate with the increased NIS expression. AKT V+ arsenic acid induces an increased rate of apoptosis due to synergism between bothsubstances.
-HMG-CoA-Reductase-Inhibitor: Mevinolin proved to be the most effective substance in this study. The 125I-Iodid-uptake is statistically significant increased, along with an increased NIS-Expression after 48h. The rate of cell proliferation is decreased and the rate of apoptosis after 48h significantly increased.
-Histone-Deacetylase-Inhibitor: (Apicidin, valproic acid, APHA Compound 8): Only Apicidin induces a significantly increased 125I-Iodid-uptake. All 3 Histone-Deacetylase-Inhibitors cause an decreased NIS and Pendrin expression after 24h and an increased expression after 48h. Additionally a slightly increased 3H-Thymidine- uptake is measured. Histone-Deacetylase-Inhibitors did not influence cell apotosis.
-Troglitazon: 125I-Iodid- and 3H-Thymidine- uptake is increased. The results of the immuncytochemistry show an increase in NIS and Pendrin expression. Troglitazon did not influence apoptosis.