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
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.
Available from: Sook-Kyoung Heo
- "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 . There were also earlier reports of VPA inducing cell cycle arrest and apoptosis in hepatoma , prostate carcinoma  and thyroid cancer cells . Studies have also revealed the anti-leukemic activity of VPA in human Philadelphia chromosome-positive acute lymphatic and CML cells  and in AML cells expressing P-glycoprotein and multidrug resistance-associated protein 1 . "
[Show abstract] [Hide abstract]
ABSTRACT: Dasatinib is a compound developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor against wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA) is an anti-epileptic drug that also acts as a class I histone deacetylase inhibitor. The aim of this research was to determine the anti-leukemic effects of dasatinib and VPA in combination and to identify their mechanism of action in acute myeloid leukemia (AML) cells. Dasatinib was found to exert potent synergistic inhibitory effects on VPA-treated AML cells in association with G1 phase cell cycle arrest and apoptosis induction involving the cleavage of poly (ADP-ribose) polymerase and caspase-3, -7 and -9. Dasatinib/VPA-induced cell death thus occurred via caspase-dependent apoptosis. Moreover, MEK/ERK and p38 MAPK inhibitors efficiently inhibited dasatinib/VPA-induced apoptosis. The combined effect of dasatinib and VPA on the differentiation capacity of AML cells was more powerful than the effect of each drug alone, being sufficiently strong to promote AML cell death through G1 cell cycle arrest and caspase-dependent apoptosis. MEK/ERK and p38 MAPK were found to control dasatinib/VPA-induced apoptosis as upstream regulators, and co-treatment with dasatinib and VPA to contribute to AML cell death through the regulation of differentiation capacity. Taken together, these results indicate that combined dasatinib and VPA treatment has a potential role in anti-leukemic therapy.
Available from: Eleonore Froehlich
- "In-vitro  Trichostatin A Increase of NIS-mRNA; cell growth (M) "
[Show abstract] [Hide abstract]
ABSTRACT: Targeted therapy pinpointing specific alteration in cancer cells has gained an important role in the treatment of cancer. Compounds that re-induce thyroid-specific functions could be particularly useful in differentiated thyroid cancers by rendering them susceptible to radioiodine treatment, which is relatively specific and has few adverse effects. This review describes the rationale for radioiodine treatment, considering the targets of compounds with differentiation-inducing effects, and the impact of these drugs on the expression of thyroid-specific proteins and on iodine-uptake. We survey the results from the clinical trials thus far performed. We conclude that although retinoids, thiazolidinediones, histone deacetylase inhibitors and DNA methyltransferase inhibitors do increase the expression of thyroid-specific proteins, their clinical efficacy is limited. The relatively low rate of remissions in clinical trials with re-differentiating compounds could be due to low levels of the target, heterogeneity of iodine uptake into the tumor, poor correlation of radioiodine uptake and clinical remission, and/or the slow onset of the therapeutic effect. Although the mode of action is not clear, the combination of tyrosine kinase inhibitors and RAI treatment could improve clinical responses in non-radioiodine avid metastatic thyroid carcinoma.
Available from: Dennie Jones
- "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       . Valproic acid has displayed potent in vitro and in vivo antitumor activities against neuroblastoma, glioma, leukemia, breast cancer, multiple myeloma, and prostate cancer lines         . 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. "
[Show abstract] [Hide abstract]
ABSTRACT: Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.