Shen Wen T, Wong Ted S, Chung Woong-Youn, Wong Mariwil G, Kebebew Electron, Duh Quan-Yang, Clark Orlo H
Department of Surgery, Endocrine Surgery Laboratory, UCSF/Mt. Zion Medical Center, San Francisco, CA 94143-1674, USA.
Surgery. 2005 Dec;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.
组蛋白去乙酰化酶抑制剂是甲状腺癌最有前景的新疗法之一。丙戊酸（VA）是一种抗惊厥药，能在无毒浓度下抑制组蛋白去乙酰化酶活性。我们推测VA对人甲状腺癌细胞具有抗肿瘤作用。
我们用VA（0.5 - 2 mmol/L）处理1个乳头状和3个滤泡状甲状腺癌细胞系24至72小时。用细胞增殖检测试剂盒测量细胞增殖。用膜联蛋白V - 异硫氰酸荧光素定量正在发生凋亡的细胞。用定量聚合酶链反应测量凋亡调节和分化基因的表达。
48小时时，VA使所有细胞系的生长抑制26%至59%，72小时时高达77%。经VA处理的细胞中有19%至30%发生凋亡，而对照细胞为4%至8%。促生存基因bcl - 2和bcl - xl的表达下调10%至60%；促凋亡基因bax的表达上调23%至85%。在滤泡状细胞系中，钠碘同向转运体和甲状腺球蛋白信使核糖核酸表达上调93%至370%，但在乳头状细胞系中保持不变。
VA抑制甲状腺癌细胞生长，诱导凋亡，并调节凋亡调节和分化基因表达。这些发现表明VA在临床上可能对滤泡细胞源性甲状腺癌患者有用。
