This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Catalano, M. G. Articles by Boccuzzi, G. Search for Related Content PubMed PubMed Citation Articles by Catalano, M. G. Articles by Boccuzzi, G. Related Collections Thyroid Endocrine Oncology

Valproic Acid Induces Apoptosis and Cell Cycle Arrest in Poorly Differentiated Thyroid Cancer Cells

Oncological Endocrinology (M.G.C., N.F., M.P., L.C., R.P., G.B.), Azienda Sanitaria Ospedaliera, San Giovanni Battista, and Department of Clinical Pathophysiology (M.G.C., O.B., G.B.), University of Turin, 10126 Turin, Italy

Address all correspondence and requests for reprints to: Prof. Giuseppe Boccuzzi, Dipartimento di Fisiopatologia Clinica, Via Genova 3, 10126 Torino, Italy. E-mail: giuseppe.boccuzzi{at}unito.it.

Poorly differentiated thyroid carcinoma is an aggressive human cancer that is resistant to conventional therapy. Histone deacetylase inhibitors are a promising class of drugs, acting as antiproliferative agents by promoting differentiation, as well as inducing apoptosis and cell cycle arrest. Valproic acid (VPA), a class I selective histone deacetylase inhibitor widely used as an anticonvulsant, promotes differentiation in poorly differentiated thyroid cancer cells by inducing Na⁺/I^– symporter 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; caspases 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 redifferentiation 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.

This article has been cited by other articles:

				I. Ecke, F. Petry, A. Rosenberger, S. Tauber, S. Monkemeyer, I. Hess, C. Dullin, S. Kimmina, J. Pirngruber, S. A. Johnsen, et al. Antitumor Effects of a Combined 5-Aza-2'Deoxycytidine and Valproic Acid Treatment on Rhabdomyosarcoma and Medulloblastoma in Ptch Mutant Mice Cancer Res., February 1, 2009; 69(3): 887 - 895. [Abstract] [Full Text] [PDF]

				M. G Catalano, R. Poli, M. Pugliese, N. Fortunati, and G. Boccuzzi Valproic acid enhances tubulin acetylation and apoptotic activity of paclitaxel on anaplastic thyroid cancer cell lines Endocr. Relat. Cancer, September 1, 2007; 14(3): 839 - 845. [Abstract] [Full Text] [PDF]

				D. Y. Greenblatt, A. M. Vaccaro, R. Jaskula-Sztul, L. Ning, M. Haymart, M. Kunnimalaiyaan, and H. Chen Valproic Acid Activates Notch-1 Signaling and Regulates the Neuroendocrine Phenotype in Carcinoid Cancer Cells Oncologist, August 1, 2007; 12(8): 942 - 951. [Abstract] [Full Text] [PDF]

				Q. Yang, Y. Tian, S. Liu, R. Zeine, A. Chlenski, H. R. Salwen, J. Henkin, and S. L. Cohn Thrombospondin-1 Peptide ABT-510 Combined with Valproic Acid Is an Effective Antiangiogenesis Strategy in Neuroblastoma Cancer Res., February 15, 2007; 67(4): 1716 - 1724. [Abstract] [Full Text] [PDF]

				M. G Catalano, N. Fortunati, M. Pugliese, R. Poli, O. Bosco, R. Mastrocola, M. Aragno, and G. Boccuzzi Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells. J. Endocrinol., November 1, 2006; 191(2): 465 - 472. [Abstract] [Full Text] [PDF]

				X. Huang and B. Guo Adenomatous polyposis coli determines sensitivity to histone deacetylase inhibitor-induced apoptosis in colon cancer cells. Cancer Res., September 15, 2006; 66(18): 9245 - 9251. [Abstract] [Full Text] [PDF]

				A. Y. M. Au, C. McBride, K. G. Wilhelm Jr., R. J. Koenig, B. Speller, L. Cheung, M. Messina, J. Wentworth, V. Tasevski, D. Learoyd, et al. PAX8-Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) Disrupts Normal PAX8 or PPAR{gamma} Transcriptional Function and Stimulates Follicular Thyroid Cell Growth Endocrinology, January 1, 2006; 147(1): 367 - 376. [Abstract] [Full Text] [PDF]