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Paper 2 (0830)
VALPROIC ACID INHIBITS GROWTH, INDUCES APOPTOSIS AND MODULATES GENE EXPRESSION OF THYROGLOBULIN AND THE SODIUM-IODIDE SYMPORTER IN HUMAN THYROID CANCER CELLS
Background: Among the most promising new therapies for the treatment of thyroid cancer are the histone deacetylase inhibitors, a group of heterogeneous compounds with antiproliferative and redifferentiating effects. Valproic acid (VA) is a widely used, well-tolerated anticonvulsant medication that has been demonstrated to exhibit histone deacetylase-inhibiting activity at non-toxic concentrations. We hypothesized that VA would have antineoplastic effects on human thyroid cancer cells.
The 26th Annual Meeting of the American
Association of Endocrine Surgeons
April 3rd- 5th,2005 - Paradisus Riviera Cancun.
Wen Shen MD, Ted Wong PhD, Mariwil Wong BS, Electron Kebebew MD, Quan-Yang Duh MD, Orlo Clark MD
University of California San Francisco
Design: We used 3 follicular thyroid cancer cell lines (FTC-133, FTC-236, FTC-238) and a papillary thyroid cancer cell line (TPC-1); the cells were treated with VA at doses of 0.5-2 mM for 24, 48, and 72 hours. Cell proliferation was measured using the Cyquant assay. Flow cytometry with Annexin-FITC labeling was used to quantitate the percentage of cells undergoing apoptosis. Quantitative PCR was used to measure changes in the expression of apoptosis-regulatory and differentiation gene markers.
Results: Treatment with VA inhibited growth in all 4 thyroid cancer cell lines by 40-53% at 48 hours and 60-76% at 72 hours (p<0.05). 17-30% of VA-treated papillary and follicular thyroid cancer cells underwent apoptosis by 72 hours, compared with 4-8% of untreated controls (p<0.05). In the 4 cell lines, expression of the pro-apoptosis gene bax was upregulated by 23-90%, while expression of the pro-survival genes bcl-2 and bcl-xl was downregulated by 10-51% (p<0.05). Sodium-iodide symporter (NIS) and thyroglobulin mRNA expression were upregulated by 93-370% in the follicular thyroid cancer cell lines but were not significantly changed in the papillary thyroid cancer cell line.
Conclusions: VA inhibits growth, induces apoptosis and modulates apoptosis-regulatory and differentiation gene marker expression levels in thyroid cancer cells. These antineoplastic effects of VA suggest that it would be clinically useful for the treatment of patients with incurable thyroid cancers of follicular cell origin.