Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells

Abstract

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 antineoplastic 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 G 2 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.

Histone deacetylase inhibitors induce thymidine phosphorylase expression in cultured breast cancer cell lines

“…preclinical and clinical data indicate that HDACi may interfere with the expression of pro-and anti-angiogenic genes, suggesting a synergistic effect when HDACi are combined with anti-angiogenic agents such as the anti-VEGF antibody, bevacizumab (28). In addition, HDACi have been observed to potentiate the cytotoxicity of anthracycline-type topoisomerase (topo) II inhibitors such as doxorubicin, epirubicin and mitoxanthrone (29)(30)(31). our data suggest that HDACi potentially sensitize tumor cells to treatment with capecitabine by enhancing the expression of TP.…”

Overview of the Classical Histone Deacetylase Enzymes and Histone Deacetylase Inhibitors

“…For example, Trichostatin A has been shown to augment doxorubicin-induced apoptosis and cell death in human erythroleukemic K562 cells, anaplastic thyroid carcinoma, and A549 alveolar adenocarcinoma cells [60,61]. Similarly, SAHA and valproic acid have been shown to enhance the sensitivity of malignant cells to the effects of doxorubicin [62,63]. HDAC inhibitors induce histone hyperacetylation, resulting in a more open transcriptionally permissive chromatin conformation, a phenomenon that has been verified by MNase digestion assays [64].…”

Alternative Medical Treatment for Radioiodine-Refractory Thyroid Cancers

“…Although the real effectiveness of HDAC inhibitors is still a question, combination therapy with HDAC inhibitors and other agents may be an answer. In several in vitro studies, an enhanced effect was observed with combination therapy, such as depsipeptide combined with p53 gene therapy [32], doxorubicin combined with VPA [33], and HDAC inhibitors combined with proteasome inhibitor [34]. Particularly SAHA showed a synergistic effect with all of the target therapy agents in a cell study [35].…”