Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells

  • Leukemia. 2015 Jun;29(6):1267-78. doi: 10.1038/leu.2014.340.
W Fiskus  1 ,  S Sharma  2 ,  S Saha  1 ,  B Shah  1 ,  S G T Devaraj  1 ,  B Sun  1 ,  S Horrigan  3 ,  C Leveque  1 ,  Y Zu  1 ,  S Iyer  1 ,  K N Bhalla  1
Affiliations
  • 1. Houston Methodist Research Institute, Houston, TX, USA.
  • 2. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • 3. Beta Cat Pharmaceutical, Gaithersburg, MD, USA.
PMID: 25482131 DOI: 10.1038/leu.2014.340
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.

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