Effect of valproic acid on miRNAs affecting histone deacetylase in a model of anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxelin vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered withEudraCT 2008-005221-11.

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Effects of the histone deacetylase inhibitor valproic acid on the sensitivity of anaplastic thyroid cancer cell lines to imatinib

Oncology Reports ◽

10.3892/or_00000252 ◽

2009 ◽

Author(s):

Boccuzzi

Keyword(s):

Valproic Acid ◽

Thyroid Cancer ◽

Histone Deacetylase ◽

Cell Lines ◽

Cancer Cell ◽

Histone Deacetylase Inhibitor ◽

Anaplastic Thyroid Cancer ◽

Thyroid Cancer Cell ◽

Deacetylase Inhibitor ◽

Thyroid Cancer Cell Lines

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

Journal of Endocrinology ◽

10.1677/joe.1.06970 ◽

2006 ◽

Vol 191 (2) ◽

pp. 465-472 ◽

Cited By ~ 73

Author(s):

Maria G Catalano ◽

Nicoletta Fortunati ◽

Mariateresa Pugliese ◽

Roberta Poli ◽

Ornella Bosco ◽

...

Keyword(s):

Valproic Acid ◽

Thyroid Cancer ◽

Histone Deacetylase ◽

Topoisomerase Ii ◽

Human Cancer ◽

Combined Therapy ◽

Survival Rates ◽

Hdac Inhibitors ◽

Anaplastic Thyroid Cancer ◽

Anaplastic Thyroid Carcinoma

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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Effect of Valproic Acid on miRNAs Affecting Histone Deacetylase in a Model of Anaplastic Thyroid Cancer

10.21203/rs.3.rs-548056/v1 ◽

2021 ◽

Author(s):

Nur Selvi Günel ◽

Nihal Birden ◽

Cansu Çalışkan Kurt ◽

Bakiye Göker Bağca ◽

behrouz shademan ◽

...

Keyword(s):

Valproic Acid ◽

Thyroid Cancer ◽

Histone Deacetylase ◽

Expression Patterns ◽

Endocrine System ◽

Anaplastic Thyroid Cancer ◽

Anaplastic Thyroid Carcinoma ◽

Rt Pcr ◽

Surgical Interventions ◽

Genes Expression

Abstract Thyroid cancer is the most common malignant tumor of the endocrine system seen in the thyroid gland. More than 90% of thyroid cancers comprise papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although anaplastic thyroid carcinoma (ATC) accounts for less than 2% of thyroid cancer. But patients' lifespan after diagnosis is about 6 months. Surgical interventions, radioactive iodine use, and chemotherapy are not sufficient in the treatment of ATC, so alternative therapies are needed. The WST-1 assay test was performed to evaluate the anti-proliferative effects of Valproic acid (VPA). Also, Effect of VPA on miRNAs affecting histone deacetylase were determined by Quantitative RT-PCR. In BRAFV600E / mut SW1736 (SW1736) cell line IC50 dose for VPA found 1.6 mg/ml. in our study, the level of oncogenic genes expression in cells treated with VPA, including miR-184, miR-222-5p, miR-124-3p, and miR-328-3p, decreased. Also, the expression of tumor inhibitory genes is miR-323-5p, miR-182-5p, miR-138-5p, miR-217, miR-15a-5p, miR-29b-3p, miR-324-5p and miR-101- 5p increased significantly. VPA can ad-just countless gene expression patterns, including microRNAs (miRNAs), by targeting histone deacetylase (HDAC). We got very promising results with VPA.

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The novel histone deacetylase inhibitor thailandepsin A inhibits anaplastic thyroid cancer growth

Journal of Surgical Research ◽

10.1016/j.jss.2014.02.042 ◽

2014 ◽

Vol 190 (1) ◽

pp. 191-197 ◽

Cited By ~ 20

Author(s):

Eric Weinlander ◽

Yash Somnay ◽

April D. Harrison ◽

Cheng Wang ◽

Yi-Qiang Cheng ◽

...

Keyword(s):

Thyroid Cancer ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitor ◽

Anaplastic Thyroid Cancer ◽

Cancer Growth ◽

The Novel ◽

Deacetylase Inhibitor

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Histone Deacetylase Inhibition Modulates E-Cadherin Expression and Suppresses Migration and Invasion of Anaplastic Thyroid Cancer Cells

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-2970 ◽

2012 ◽

Vol 97 (7) ◽

pp. E1150-E1159 ◽

Cited By ~ 29

Author(s):

Maria Graziella Catalano ◽

Nicoletta Fortunati ◽

Mariateresa Pugliese ◽

Francesca Marano ◽

Loredana Ortoleva ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Histone Deacetylase ◽

Anaplastic Thyroid Cancer ◽

Migration And Invasion ◽

Histone Deacetylase Inhibition ◽

Thyroid Cancer Cells ◽

E Cadherin

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The Beneficial Effects of Valproic Acid in Thyroid Cancer Are Mediated through Promoting Redifferentiation and Reducing Stemness Level: AnIn VitroStudy

Journal of Thyroid Research ◽

10.1155/2014/218763 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Vahid Haghpanah ◽

Mohsen Malehmir ◽

Bagher Larijani ◽

Shahin Ahmadian ◽

Kamran Alimoghaddam ◽

...

Keyword(s):

Valproic Acid ◽

Thyroid Cancer ◽

Cell Lines ◽

Colony Formation ◽

Morphological Changes ◽

Anaplastic Thyroid Cancer ◽

Human Thyroid ◽

Marker Genes ◽

Specific Marker ◽

Hoechst 33342

Valproic acid (VPA) has been identified as a histone deacetylase inhibitor, inducing differentiation in transformed cells. However, no study has shown the effect of VPA in the redifferentiation induction and stemness of anaplastic thyroid. The main objective of this study was to evaluate the efficacy of VPA as a differentiation therapy agent in human thyroid cancer based on its effect on stemness and differentiation process. Indications for differentiation of 8305C and B-CPAP cell lines following VPA treatment were obtained by analyzing cell proliferation rate, morphological changes, adherent-dependent colony formation, and Hoechst 33342 staining. The expressions of stemness, differentiation, and aggressiveness specific marker genes were measured by quantitative RT-PCR. VPA treatment effectively showed growth inhibition in both cell lines. The high nuclear-cytoplasmic (N : C) ratio of 8305C cells markedly decreased and treated cells became more epithelial-like. Treated cells showed stronger Hoechst 33342 fluorescence compared with control cells. The hTERT and OCT-4 reduction was paralleled with adherent-dependent colony formation decrement in both cell lines. VPA effectively induced NIS and TTF-1 in anaplastic cells, it whereas showed no clear pattern in papillary cell line. VPA treatment also resulted in the reduction of MMP-2 and MMP-9. These finding suggest that VPA could redifferentiate the anaplastic thyroid cancer cells.

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