MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells
MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells
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DOI：
10.1016/j.leukres.2008.02.018
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发表时间：
2008-09-01
影响因子：
2.7
通讯作者：
Yokoyama, Akihito
中科院分区：
文献类型：
--
作者：
Nishioka, Chie;Ikezoe, Takayuki;Yokoyama, Akihito
本研究探讨了一种新型组蛋白去乙酰化酶抑制剂（HDACI） MS-275对多种具有明确遗传改变的人类白血病细胞的作用。MS-275在培养第2天通过3-（4,5-二甲基噻唑-2-基）- 2,5 -二苯基溴化四唑测定，深度诱导具有fms样酪氨酸激酶3 （FLT3）基因（FLT3- itd）内部串联重复突变的急性髓性白血病（AML） MOLM13和双表型白血病mv1 -11细胞生长阻滞，ic50小于1 μ M。将这些细胞暴露于MS-275中会降低FLT3的总水平和磷酸化形式，导致其下游信号通路失活，包括Akt、ERK和STAT5。进一步的研究发现MS-275诱导热休克蛋白90 （HSP90）乙酰化，并结合FLT3泛素化，导致FLT3蛋白在这些细胞中降解。用蛋白酶体抑制剂硼替佐米治疗后，这种现象减弱，证实FLT通过泛素/蛋白酶体途径降解。此外，我们发现进一步抑制MEK/ERK信号传导可增强MS-275在白血病细胞中的作用。综上所述，MS-275可能对具有FLT3基因激活突变的白血病患者有效。(C) 2008 Elsevier Ltd版权所有。
This study explored the effect of MS-275, a novel histone deacetylase inhibitor (HDACI), against a variety of human leukemia cells with defined genetic alterations. MS-275 profoundly induced growth arrest of acute myelogenous leukemia (AML) MOLM13 and biphenotypic leukemia MV4-11 cells, which possess internal tandem duplication mutation in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD), with IC50s less than 1 mu M, as measured by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay on day two of culture. Exposure of these cells to MS-275 decreased levels of total, as well as, phosphorylated forms of FLT3, resulting in inactivation of its downstream signal pathways, including Akt, ERK, and STAT5. Further studies found that MS-275 induced acetylation of heat shock protein 90 (HSP90) in conjunction with ubiquitination of FLT3, leading to degradation of FLT3 proteins in these cells. This was blunted by treatment with the proteasome inhibitor bortezomib, confirming that FLT was degraded via ubiquitin/proteasome pathway. Moreover, we found that further inhibition of MEK/ERK signaling potentiated the action of MS-275 in leukemia cells. Taken together, MS-275 may be useful for treatment of individuals with leukemia possessing activating mutation of FLT3 gene. (C) 2008 Elsevier Ltd. All rights reserved.