Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells
Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells
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DOI：
10.1038/leu.2008.243
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发表时间：
2008-12-01
期刊：
影响因子：
11.4
通讯作者：
Yokoyama, A.
中科院分区：
文献类型：
--
作者：
Nishioka, C.;Ikezoe, T.;Yokoyama, A.
这项研究发现，MS-275，一种新型的合成苯甲酰胺组蛋白去乙酰化酶抑制剂（HDACI），阻断Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号在急性髓性白血病（AML）HL 60和急性早幼粒细胞白血病（APL）NB 4细胞，通过降低磷酸化（p）-Akt，p-p70核糖体S6激酶（p70 S6 K）和p-S6 K水平的蛋白质印迹分析评估。有趣的是，雷帕霉素类似物RAD 001（依维莫司）对mTOR的进一步失活显著增强了MS-275介导的这些细胞的生长抑制和凋亡，同时增强了p27（kip 1）的上调和c-Myc的下调。此外，RAD 001增强MS-275诱导HL 60和NB 4细胞分化的能力，如通过CD 11b细胞表面抗原的表达以及硝基蓝四唑的减少所测量的。重要的是，RAD 001增强了MS-275诱导这些细胞中髓样分化相关转录因子CCAAT增强子结合蛋白的表达的能力，这与其启动子上组蛋白H3的乙酰化增强有关。此外，RAD 001（5 mg/kg）显著增强MS-275（10 mg/kg）抑制裸鼠中HL 60肿瘤异种移植物增殖的作用，而没有副作用。总之，HDACI和mTOR抑制剂的伴随施用可能是患有人类白血病子集的个体的有希望的治疗策略。
This study found that MS-275, a novel synthetic benzamide histone deacetylase inhibitor (HDACI), blocked Akt/mammalian target of rapamycin (mTOR) signaling in acute myelogenous leukemia (AML) HL60 and acute promyelocytic leukemia (APL) NB4 cells, as assessed by decreased levels of the phosphorylated (p)-Akt, p-p70 ribosomal S6 kinase (p70S6K) and p-S6K by western blot analysis. Interestingly, further inactivation of mTOR by rapamycin analog RAD001 (everolimus) significantly enhanced MS-275-mediated growth inhibition and apoptosis of these cells in parallel with enhanced upregulation of p27(kip1) and downregulation of c-Myc. In addition, RAD001 potentiated the ability of MS-275 to induce differentiation of HL60 and NB4 cells, as measured by the expression of CD11b cell surface antigens, as well as reduction of nitroblue tetrazolium. Importantly, RAD001 potentiated the ability of MS-275 to induce the expression of the myeloid differentiation-related transcription factor, CCAAT enhancer-binding protein-epsilon, in these cells in association with enhanced acetylation of histone H3 on its promoter. Furthermore, RAD001 (5 mg/kg) significantly enhanced the effects of MS-275 (10 mg/kg) to inhibit proliferation of HL60 tumor xenografts in nude mice without adverse effects. Taken together, concomitant administration of an HDACI and an mTOR inhibitor may be a promising treatment strategy for the individuals with a subset of human leukemia.