Savickiene Jurate, Treigyte Grazina, Magnusson Karl-Eric, Navakauskiene Ruta
Department of Developmental Biology, Institute of Biochemistry, Vilnius, Lithuania.
Ann N Y Acad Sci. 2009 Aug;1171:321-33. doi: 10.1111/j.1749-6632.2009.04718.x.
Acute promyelocytic leukemia KG1 cells with t(11;17) PLZF-RARalpha respond poorly to the differentiation inducer all-trans retinoic acid (RA), and the reason for the RA resistance is the recruitment of histone deacetylase by PLZF-RARalpha. Here, we demonstrate that histone deacetylase inhibitors (HDACIs), FK228, BML-210, phenyl butyrate, and vitamin B3, in different combinations with RA, act as KG1 cell growth inhibitors. Partial differentiation to granulocytes was induced by 3 micromol/L RA, and its combination with HDAC inhibitors did not enhance RA-induced but potentiated apoptosis. HDACIs induced accumulation of hyperacetylated histone H4. Chromatin immunoprecipitation analysis has revealed phenyl butyrate and its combinations with RA and vitamin B3 cause histone H4 acetylation in the p21 promoter regions corresponding to p53 and/or Sp1 sites. This was coincident with the activation of the transcription factor p53-binding activity to the p21 promoter in electrophoretic mobility shift assay. The results indicate the possibility of using the combination of agents for therapeutic strategy in RA-resistant acute myeloid leukemia to produce both differentiation and apoptosis.
伴有t(11;17) PLZF-RARα的急性早幼粒细胞白血病KG1细胞对分化诱导剂全反式维甲酸（RA）反应不佳，RA耐药的原因是PLZF-RARα募集组蛋白脱乙酰酶。在此，我们证明组蛋白脱乙酰酶抑制剂（HDACIs）FK228、BML-210、苯丁酸钠和维生素B3与RA以不同组合形式可作为KG1细胞生长抑制剂。3 μmol/L RA诱导部分细胞分化为粒细胞，其与HDAC抑制剂联合使用并未增强RA诱导的分化，但增强了细胞凋亡。HDACIs诱导了高乙酰化组蛋白H4的积累。染色质免疫沉淀分析显示，苯丁酸钠及其与RA和维生素B3的组合可导致p21启动子区域对应于p53和/或Sp1位点的组蛋白H4乙酰化。这与电泳迁移率变动分析中转录因子p53与p21启动子结合活性的激活相一致。结果表明，联合使用这些药物有可能用于对RA耐药的急性髓性白血病的治疗策略，以同时诱导分化和凋亡。
