1. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells.
- Author
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Fiskus, W, Sharma, S, Saha, S, Shah, B, Devaraj, S G T, Sun, B, Horrigan, S, Leveque, C, Zu, Y, Iyer, S, and Bhalla, K N
- Subjects
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ANIMAL experimentation , *ANTINEOPLASTIC agents , *APOPTOSIS , *BIOLOGICAL models , *CELL physiology , *CYTOSKELETAL proteins , *DRUG synergism , *ENZYME inhibitors , *HYDROLASES , *MICE , *RESEARCH funding , *WESTERN immunoblotting , *ACUTE myeloid leukemia , *CANCER cell culture , *PRECIPITIN tests , *PHARMACODYNAMICS - Abstract
The canonical wingless-type MMTV integration site (WNT)-β-catenin pathway is essential for self-renewal, growth and survival of acute myeloid leukemia (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 T-cell factor (TCF) 4/lymphoid enhancer factor 1 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 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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