Valproic acid inhibits growth, induces apoptosis, and modulates apoptosis-regulatory and differentiation gene expression in human thyroid cancer cells

Department of Surgery, University of California, San Francisco, San Francisco, California, United States
Surgery (Impact Factor: 3.38). 01/2006; 138(6):979-84; discussion 984-5. DOI: 10.1016/j.surg.2005.09.019
Source: PubMed


Among the most promising new therapies for thyroid cancer are the histone deacetylase inhibitors. Valproic acid (VA) is an anticonvulsant that inhibits histone deacetylase activity at nontoxic concentrations. We hypothesized that VA would have antineoplastic effects on human thyroid cancer cells.
We treated 1 papillary and 3 follicular thyroid cancer cell lines with VA (0.5-2 mmol/L) for 24 to 72 hours. Cell proliferation was measured with a cell proliferation assay kit. Annexin V-fluorescein isothiocyanate was used to quantitate cells that were undergoing apoptosis. Quantitative polymerase chain reaction was used to measure expression of apoptosis-regulatory and differentiation genes.
VA inhibited growth in all cell lines by 26% to 59% at 48 hours and up to 77% at 72 hours. Nineteen percent to 30% of VA-treated cells underwent apoptosis, compared with 4% to 8% of the control cells. Expression of pro survival genes bcl-2 and bcl-xl was down-regulated by 10% to 60%; expression of the proapoptosis gene bax was up-regulated by 23% to 85%. Sodium-iodide symporter and thyroglobulin messenger RNA expression were up-regulated by 93% to 370% in follicular cell lines but remained unchanged in the papillary cell line.
VA inhibits growth, induces apoptosis, and modulates apoptosis-regulatory and differentiation gene expression in thyroid cancer cells. These findings suggest that VA may be useful clinically for patients with thyroid cancers of follicular cell origin.

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    • "Interest in the use of such inhibitors as anti-cancer agents was recently sparked by research showing them to strongly induce cell cycle arrest, differentiation and malignant cell apoptosis [10]. There were also earlier reports of VPA inducing cell cycle arrest and apoptosis in hepatoma [11], prostate carcinoma [12] and thyroid cancer cells [13]. Studies have also revealed the anti-leukemic activity of VPA in human Philadelphia chromosome-positive acute lymphatic and CML cells [14] and in AML cells expressing P-glycoprotein and multidrug resistance-associated protein 1 [15]. "
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    • "After treatment with valproic acid, there is altered expression of multiple genes, including the cyclin-dependent kinase inhibitor p21Cip1, glycogen synthase kinase-3ß, and peroxisome proliferatoractivated receptors, and down-regulation of the expression of the antiapoptotic protein kinase C α and ε isoforms [33] [34] [35] [36] [37] [38] [39]. Valproic acid has displayed potent in vitro and in vivo antitumor activities against neuroblastoma, glioma, leukemia, breast cancer, multiple myeloma, and prostate cancer lines [9] [40] [41] [42] [43] [44] [45] [46] [47]. Even though valproic acid is a potent teratogen in noncommitted cell lineages, it is otherwise usually well tolerated; in fact, it may even protect against neurotoxicity observed with some drugs. "
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