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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Shen
Wen T
WT
Department of Surgery, Endocrine Surgery Laboratory, UCSF/Mt. Zion Medical Center, San Francisco, CA 94143-1674, USA.
Wong
Ted S
TS
Chung
Woong-Youn
WY
Wong
Mariwil G
MG
Kebebew
Electron
E
Duh
Quan-Yang
QY
Clark
Orlo H
OH
D018263:Adenocarcinoma, Follicular / Q000378:metabolism / Q000473:pathology*; D000231:Adenocarcinoma, Papillary / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D013954:Thyroglobulin / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D014635:Valproic Acid / Q000494:pharmacology*; D000099209:Sodium-Iodide Symporters
D051017:Apoptosis Regulatory Proteins; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D027981:Symporters; D013954:Thyroglobulin; D014635:Valproic Acid; D000099209:Sodium-Iodide Symporters