Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells.
Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells.
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经典的WNT-β-catenin通路对于AML干/母细胞祖细胞（BPC）的自我更新、生长和存活是必不可少的。WNT信号转导失调抑制β-连环蛋白的降解，导致AML BPC中β-连环蛋白与转录调节因子TCF 4/LEF 1的核转位和辅因子活性增加。在这里，我们确定了蒽醌肟类似物BC 2059（BC）的临床前抗AML活性，已知其减弱β-连环蛋白水平。BC处理破坏了β-连环蛋白与支架蛋白TBL 1（transducin β-like 1）的结合，蛋白酶体降解和β-连环蛋白核水平的下降。这与TCF 4的转录活性降低及其靶基因cyclin D1、c-MYC和survivin的表达有关。BC处理剂量依赖性地诱导培养的和原代AML BPC的凋亡。BC治疗还显著改善了移植有显示β-连环蛋白核表达的培养或原代AML BPC的免疫耗竭小鼠的中位生存期。用泛组蛋白脱乙酰酶抑制剂帕比司他和BC的共处理协同诱导培养的和原代AML BPC的凋亡，包括表达FLT 3-ITD的那些，以及进一步显著改善移植有原代AML BPC的免疫耗竭小鼠的存活。这些发现强调了有希望的临床前活性，并保证进一步测试BC对人类AML，特别是那些表达FLT 3-ITD的人。
The canonical WNT-β-catenin pathway is essential for self-renewal, growth and survival of AML stem/blast progenitor cells (BPCs). Deregulated WNT signaling inhibits degradation of β-catenin, causing increased nuclear translocation and co-factor activity of β-catenin with the transcriptional regulator TCF4/LEF1 in AML BPCs. Here, we determined the pre-clinical anti-AML activity of the anthraquinone oxime-analog BC2059 (BC), known to attenuate β-catenin levels. BC treatment disrupted the binding of β-catenin with the scaffold protein TBL1 (transducin β-like 1) and proteasomal degradation and decline in the nuclear levels of β-catenin. This was associated with reduced transcriptional activity of TCF4 and expression of its target genes, cyclin D1, c-MYC and survivin. BC treatment dose-dependently induced apoptosis of cultured and primary AML BPCs. Treatment with BC also significantly improved the median survival of immune-depleted mice engrafted with either cultured or primary AML BPCs exhibiting nuclear expression of β-catenin. Co-treatment with the pan-histone deacetylase inhibitor panobinostat and BC synergistically induced apoptosis of cultured and primary AML BPCs, including those expressing FLT3-ITD, as well as further significantly improved the survival of immune-depleted mice engrafted with primary AML BPCs. These findings underscore the promising pre-clinical activity and warrant further testing of BC against human AML, especially those expressing FLT3-ITD.
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影响因子：
14.8
作者：
Bradner, James E.;West, Nathan;Grachan, Melissa L.;Greenberg, Edward F.;Haggarty, Stephen J.;Warnow, Tandy;Mazitschek, Ralph
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Weissman, IL
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