Department of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai, People's Republic of China.
Eur J Pharm Sci. 2010 Oct 9;41(2):210-8. doi: 10.1016/j.ejps.2010.06.011. Epub 2010 Jun 25.
Valproic acid (VPA) is a broad-spectrum inhibitor of histone deacetylase, which has been used in cancer therapy. Recently, the combination of VPA with other anticancer agents has been considered as a useful and necessary strategy to specifically induce anticancer gene expression. Curcumin (Cur) is a promising natural anticancer agent that can specifically regulate the expression of NF-kappaB, bcl-2, and bax in leukemia cells. However, no literature is available on the anticancer effects of the combination of VPA and Cur. Here we show that this combination significantly increases Sp1 binding, histone H3 and H4 acetylation in the promoter region of bax, but not in that of bcl-2. This specifically up-regulates bax expression and leads to HL-60 cell proliferation arrest, sub-G1 DNA accumulation and cell death. Further studies reveal that Cur specifically activates p38 MAPK, an essential factor for Sp1 binding at the bax promoter. Moreover, both inhibition of p38 MAPK and knock-down of bax expression significantly prevent VPA and Cur-induced proliferation arrest and death in HL-60 cells. These results suggest that Cur could p38-dependently promote bax expression and hence enhance the anticancer activity of VPA in human leukemia cells.
丙戊酸（VPA）是一种组蛋白去乙酰化酶的广谱抑制剂，已被用于癌症治疗。最近，VPA 与其他抗癌药物的联合应用被认为是一种有用且必要的策略，可以特异性地诱导抗癌基因表达。姜黄素（Cur）是一种很有前途的天然抗癌药物，可特异性调节白血病细胞中 NF-κB、bcl-2 和 bax 的表达。然而，目前尚无关于 VPA 和 Cur 联合应用的抗癌作用的文献报道。在这里，我们发现这种联合应用显著增加 bax 启动子区域 Sp1 结合、组蛋白 H3 和 H4 乙酰化，但对 bcl-2 没有影响。这特异性地上调 bax 表达，导致 HL-60 细胞增殖停滞、亚 G1 DNA 积累和细胞死亡。进一步的研究表明，Cur 特异性地激活了 p38 MAPK，这是 Sp1 在 bax 启动子上结合的必需因素。此外，p38 MAPK 的抑制和 bax 表达的敲低均可显著阻止 VPA 和 Cur 诱导的 HL-60 细胞增殖停滞和死亡。这些结果表明，Cur 可以通过 p38 依赖性方式促进 bax 表达，从而增强 VPA 在人白血病细胞中的抗癌活性。
