Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: a novel potential strategy in acute myelogenous leukemia.
Selective activity of the histone deacetylase inhibitor AR-42 against leukemia stem cells: a novel potential strategy in acute myelogenous leukemia.
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DOI：
10.1158/1535-7163.mct-13-0963
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发表时间：
2014-08
影响因子：
5.7
通讯作者：
Hassane DC
中科院分区：
文献类型：
--
作者：
Guzman ML;Yang N;Sharma KK;Balys M;Corbett CA;Jordan CT;Becker MW;Steidl U;Abdel-Wahab O;Levine RL;Marcucci G;Roboz GJ;Hassane DC
大多数急性髓细胞白血病（AML）患者会复发并死于疾病。越来越多的证据表明，AML复发是由于无法根除白血病干细胞（LSC）。因此，必须确定可以消融LSC的新疗法。使用计算机基因表达为基础的筛选化合物引起类似于先前描述的抗LSC剂parthenoprotein的转录作用，我们确定了AR-42（OSU-HDAC 42），一种新的组蛋白脱乙酰酶抑制剂，其结构类似于苯丁酸酯，但在亚微摩尔浓度下具有改善的活性。在此，我们报道了AR-42诱导NF-κB抑制，破坏Hsp 90稳定其致癌客户的能力，并导致LSC而不是正常造血干细胞和祖细胞的有效和特异性细胞死亡。与孤雌激素不同，AR-42引起的caspase依赖性细胞凋亡在不激活Nrf-2驱动的细胞保护途径的情况下发生。由于AR-42已经在早期临床试验中进行了测试，我们希望我们的结果可以扩展到临床。
Most patients with acute myelogenous leukemia (AML) relapse and die of their disease. Increasing evidence indicates that AML relapse is driven by the inability to eradicate leukemia stem cells (LSC). Thus, it is imperative to identify novel therapies that can ablate LSCs. Using an in silico gene expression-based screen for compounds evoking transcriptional effects similar to the previously described anti-LSC agent parthenolide, we identified AR-42 (OSU-HDAC42), a novel histone deacetylase inhibitor that is structurally similar to phenylbutyrate, but with improved activity at submicromolar concentrations. Here, we report that AR-42 induces NF-κB inhibition, disrupts the ability of Hsp90 to stabilize its oncogenic clients, and causes potent and specific cell death of LSCs but not normal hematopoietic stem and progenitor cells. Unlike parthenolide, the caspasedependent apoptosis caused by AR-42 occurs without activation of Nrf-2-driven cytoprotective pathways. As AR-42 is already being tested in early clinical trials, we expect that our results can be extended to the clinic.