Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells.
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.
Catalano
Maria G
MG
Department of Clinical Pathophysiology, University of Turin, Via Genova 3, 10126 Turin, Italy.
Fortunati
Nicoletta
N
Pugliese
Mariateresa
M
Poli
Roberta
R
Bosco
Ornella
O
Mastrocola
Raffaella
R
Aragno
Manuela
M
Boccuzzi
Giuseppe
G
D000107:Acetylation; D000951:Antigens, Neoplasm / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy* / Q000201:enzymology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D004250:DNA Topoisomerases, Type II / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D012333:RNA, Messenger / Q000032:analysis; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D014635:Valproic Acid / Q000627:therapeutic use*
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012333:RNA, Messenger; D014635:Valproic Acid; D004317:Doxorubicin; D053148:Caspase 3; D004250:DNA Topoisomerases, Type II