Division of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA.
J Hematol Oncol. 2008 Jun 9;1:6. doi: 10.1186/1756-8722-1-6.
Histone deacetylase (HDAC) inhibitors are a new class of chemotherapeutic agents. Our laboratory has recently reported that phenylhexyl isothiocyanate (PHI), a synthetic isothiocyanate, is an inhibitor of HDAC. In this study we examined whether PHI is a hypomethylating agent and its effects on myeloma cells. RPMI8226, a myeloma cell line, was treated with PHI. PHI inhibited the proliferation of the myeloma cells and induced apoptosis in a concentration as low as 0.5 muM. Cell proliferation was reduced to 50% of control with PHI concentration of 0.5 muM. Cell cycle analysis revealed that PHI caused G1-phase arrest of RPMI8226 cells. PHI induced p16 hypomethylation in a concentration- dependent manner. PHI was further shown to induce histone H3 hyperacetylation in a concentration-dependent manner. It was also demonstrated that PHI inhibited IL-6 receptor expression and VEGF production in the RPMI8226 cells, and reactivated p21 expression. It was found that PHI induced apoptosis through disruption of mitochondrial membrane potential. For the first time we show that PHI can induce both p16 hypomethylation and histone H3 hyperacetylation. We conclude that PHI has dual epigenetic effects on p16 hypomethylation and histone hyperacetylation in myeloma cells and targets several critical processes of myeloma proliferation.
组蛋白去乙酰化酶（HDAC）抑制剂是一类新的化疗药物。我们实验室最近报道，苯己基异硫氰酸酯（PHI）是一种合成异硫氰酸酯，是 HDAC 的抑制剂。在这项研究中，我们研究了 PHI 是否是一种低甲基化剂，以及它对骨髓瘤细胞的影响。用 PHI 处理骨髓瘤细胞系 RPMI8226。PHI 以低至 0.5 μM 的浓度抑制骨髓瘤细胞的增殖并诱导其凋亡。PHI 的浓度降低至 0.5 μM 时，细胞增殖减少至对照的 50%。细胞周期分析表明，PHI 导致 RPMI8226 细胞 G1 期停滞。PHI 以浓度依赖的方式诱导 p16 低甲基化。进一步表明，PHI 以浓度依赖的方式诱导组蛋白 H3 乙酰化。还表明 PHI 抑制 RPMI8226 细胞中 IL-6 受体表达和 VEGF 产生，并重新激活 p21 表达。发现 PHI 通过破坏线粒体膜电位诱导细胞凋亡。我们首次表明，PHI 可以诱导 p16 低甲基化和组蛋白 H3 高乙酰化。我们得出结论，PHI 对骨髓瘤细胞中的 p16 低甲基化和组蛋白高乙酰化具有双重表观遗传作用，并靶向骨髓瘤增殖的几个关键过程。
