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Submitted on July 13, 2004
Accepted on November 29, 2004
Oncological Endocrinology, ASO San Giovanni Battista (M.G.C., N.F., M.P., L.C., R.P, G.B.) and Department of Clinical Pathophysiology, University of Turin (M.G.C., O.B., G.B.) Turin, Italy
* To whom correspondence should be addressed. E-mail: giuseppe.boccuzzi{at}unito.it.
Poorly differentiated thyroid carcinoma is an aggressive human cancer that is resistant to conventional therapy. HDAC inhibitors are a promising class of drugs, acting as anti-proliferative agents by promoting differentiation as well as inducing apoptosis and cell cycle arrest. Valproic acid (VPA), a class I selective HDAC inhibitor widely used as anti-convulsant, promotes differentiation in poorly differentiated thyroid cancer cells by inducing NIS and increasing iodine uptake. Here, we show that it is also highly effective at suppressing growth in poorly differentiated thyroid cancer cell lines (N-PA and BHT-101). Apoptosis induction and cell cycle arrest are the underlying mechanisms of VPA's effect on cell growth. It induces apoptosis by activating the intrinsic pathway: caspase 3 and 9 are activated, but not caspase 8. Cell cycle is selectively arrested in G1 and is associated with the increased expression of p21 and the reduced expression of cyclin A. Both apoptosis and cell cycle arrest are induced by treatment with 1 mM VPA, a dose that promotes cell re-differentiation and that is slightly above the serum concentration reached in patients treated for epilepsy. These multifaceted properties make VPA of clinical interest as a new approach to treating poorly differentiated thyroid cancer.
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