Shabbeer Shabana, Kortenhorst Madeleine S Q, Kachhap Sushant, Galloway Nathan, Rodriguez Ron, Carducci Michael A
Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland 21231, USA.
Prostate. 2007 Jul 1;67(10):1099-110. doi: 10.1002/pros.20587.
Valproic acid (VPA), is a drug approved by the FDA for epilepsy and bipolar disorders. It is a known Histone Deacetylase Inhibitor (HDACI). We tested VPA, for its anti-proliferative activity in prostate cancer (PCa) cell lines in vitro and in vivo.
DU-145 and PC-3 PCa cell lines were cultured with different doses of VPA. Cells were examined for their viability, cell cycle status and expression of cell cycle arrest, and proliferation markers. Nude mice bearing xenografts of human PCa cell lines, DU-145, and PC-3, were administered VPA in their drinking water.
VPA displayed a dose- and time-dependent anti-proliferative effect on DU-145 and PC-3 PCa cell lines in vitro. A sustained effect of the drug was seen on cell cycle arrest even at 24 hr after removal of the drug, after which the effects returned to the basal state. Administration of 0.4% w/v VPA in drinking water (resulting in 0.4 mM VPA, in plasma) was effective in inducing growth arrest, cell death, and senescence in vivo and was also anti-angiogenic. The activation of all or some of these anti-proliferative pathways may be contingent on acetylation status of histones, confirmed by detection of increased acetyl-H3K9 in VPA-treated samples when compared with untreated controls. Pharmacodynamic studies showed an increase in expression of p21 and decrease in PCNA in xenografts of VPA-treated mice compared with protein expression in untreated controls.
VPA may be functioning as an HDACI to inhibit growth of PCa cells in vitro and in vivo by modulating multiple pathways including cell cycle arrest, apoptosis, angiogenesis, and senescence.
丙戊酸（VPA）是一种经美国食品药品监督管理局（FDA）批准用于治疗癫痫和双相情感障碍的药物。它是一种已知的组蛋白去乙酰化酶抑制剂（HDACI）。我们在体外和体内测试了VPA对前列腺癌细胞系的抗增殖活性。
用不同剂量的VPA培养DU-145和PC-3前列腺癌细胞系。检测细胞的活力、细胞周期状态以及细胞周期阻滞和增殖标志物的表达。给携带人前列腺癌细胞系DU-145和PC-3异种移植瘤的裸鼠饮用含VPA的水。
VPA在体外对DU-145和PC-3前列腺癌细胞系显示出剂量和时间依赖性的抗增殖作用。即使在去除药物24小时后，仍能观察到药物对细胞周期阻滞的持续影响，之后影响恢复到基础状态。在饮用水中给予0.4% w/v的VPA（血浆中VPA浓度为0.4 mM）在体内可有效诱导生长停滞、细胞死亡和衰老，并且还具有抗血管生成作用。与未处理的对照相比，VPA处理样品中乙酰化-H3K9增加，这证实了这些抗增殖途径中全部或部分的激活可能取决于组蛋白的乙酰化状态。药效学研究表明，与未处理对照的蛋白表达相比，VPA处理小鼠的异种移植瘤中p21表达增加，PCNA表达减少。
VPA可能作为一种HDACI，通过调节包括细胞周期阻滞、凋亡、血管生成和衰老在内的多种途径，在体外和体内抑制前列腺癌细胞的生长。
