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¹ Department of Clinical Pathophysiology, University of Turin, Via Genova 3, 10126 Turin, Italy
² Oncological Endocrinology, ASO San Giovanni Battista via Genova 3, 10126 Turin, Italy
³ Department of Experimental Medicine and Oncology, University of Turin, C.so Raffaello 30, 10125 Turin, Italy

(Requests for offprints should be addressed to G Boccuzzi who is now at Dipartimento di Fisiopatologia Clinica, Via Genova 3, 10126 Torino, Italy; Email: giuseppe.boccuzzi{at}unito.it)

Multimodality treatments (i.e. surgery, chemotherapy, and radiotherapy) are recommended for anaplastic thyroid carcinoma (ATC), an extremely lethal human cancer, but to date there is little evidence that such approaches improve survival rates. It is thus necessary to seek new therapeutic tools. Histone deacetylase (HDAC) inhibitors are a promising class of anti-neoplastic agents that induce differentiation and apoptosis. Moreover, they may enhance the cytotoxicity of drugs targeting DNA through acetylation of histones. Using two ATC cell lines (CAL-62 and ARO), we show here that valproic acid (VPA), a clinically available HDAC inhibitor, enhances the activity of doxorubicin, whose anti-tumor properties involve binding to DNA and inhibiting topoisomerase II. A meager 0.7 mM VPA, which corresponds to serum concentrations in patients treated for epilepsy, is able to increase the cytotoxicity of doxorubicin about threefold in CAL-62 cells and twofold in ARO cells. The sensitizing effect, which is through histone acetylation, involves increased apoptosis, which is also shown by the increased caspase 3 activation and the enhancement of doxorubicin-induced G₂ cell cycle arrest. These results might offer a rationale for clinical studies of a new combined therapy in an effort to improve the outcome of patients with anaplastic thyroid cancer.

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