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

ABSTRACT: The canonical wingless-type MMTV integration site (WNT)-?-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 ?-catenin, causing increased nuclear translocation and co-factor activity of ?-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 ?-catenin levels. BC treatment disrupted the binding of ?-catenin with the scaffold protein transducin ?-like 1 and proteasomal degradation and decline in the nuclear levels of ?-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 ?-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.

SUBMITTER: Fiskus W 

PROVIDER: S-EPMC4456205 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature