Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
Curr Drug Targets. 2010 Mar;11(3):361-79. doi: 10.2174/138945010790711923.
Valproic acid (VPA) has been used for epilepsy treatment since the 1970s. Recently, it was demonstrated that it inhibits histone deacetylases (HDAC), modulates cell cycle, induces tumor cell death and inhibits angiogenesis in various tumor models. The exact anticancer mechanisms of VPA remains unclear, but HDAC inhibition, extracellular-regulated kinase activation, protein kinase C inhibition, Wnt-signaling activation, proteasomal degradation of HDAC, possible downregulation of telomerase activity and DNA demethylation participate in its anticancer effect. Hyperacetylation of histones, as a result of HDAC inhibition, seems to be the most important mechanism of VPA's antitumor action. Preclinical data suggest that the anticancer effect of chemotherapy is augmented when VPA is used in combination with cytostatics. Besides the effects of pretreatment with HDAC inhibitors, which increases the efficiency of 5-aza-2'-deoxycytidine, VP-16, ellipticine, doxorubicin and cisplatin, pre-exposure to VPA increases the cytotoxicity of topoisomerase II inhibitors. There are two suggested cell death mechanisms caused by potentiation of anticancer drugs by HDAC inhibitors that are neither exclusive nor synergistic. The first involves apoptosis and can be both p53 dependent or independent; the second involves mechanisms other than apoptosis. In resistant chronic myeloid leukemia (CML), VPA restores sensitivity to imatinib. We have demonstrated the synergistic effects of VPA and cisplatin in neuroblastoma cells. VPA can be taken orally, crosses the blood brain barrier and can be used for extended periods. Clinical trials in patients with malignancies are being conducted. The use of VPA prior to or together with anticancer drugs may thus prove a beneficial treatment.
丙戊酸（VPA）自 20 世纪 70 年代以来一直用于癫痫治疗。最近，它被证明可以抑制组蛋白去乙酰化酶（HDAC），调节细胞周期，诱导肿瘤细胞死亡，并抑制各种肿瘤模型中的血管生成。VPA 的确切抗癌机制尚不清楚，但 HDAC 抑制、细胞外调节激酶激活、蛋白激酶 C 抑制、Wnt 信号激活、HDAC 的蛋白酶体降解、端粒酶活性的可能下调和 DNA 去甲基化参与其抗癌作用。HDAC 抑制导致的组蛋白乙酰化似乎是 VPA 抗肿瘤作用的最重要机制。临床前数据表明，当 VPA 与细胞毒性药物联合使用时，可增强化疗的抗癌效果。除了 HDAC 抑制剂预处理增加 5-氮杂-2'-脱氧胞苷、VP-16、椭圆体、阿霉素和顺铂效率的作用外，VPA 预先暴露可增加拓扑异构酶 II 抑制剂的细胞毒性。有两种由 HDAC 抑制剂增强抗癌药物引起的细胞死亡机制，它们既不是排他的也不是协同的。第一种涉及细胞凋亡，既可以是 p53 依赖性的，也可以是 p53 非依赖性的；第二种涉及细胞凋亡以外的机制。在耐药性慢性髓性白血病（CML）中，VPA 恢复了对伊马替尼的敏感性。我们已经证明了 VPA 和顺铂在神经母细胞瘤细胞中的协同作用。VPA 可以口服、穿过血脑屏障，并且可以长期使用。正在对恶性肿瘤患者进行临床试验。因此，在使用抗癌药物之前或同时使用 VPA 可能是一种有益的治疗方法。
