title: Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells.
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.
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Fiskus
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Saha
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Shah
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: S G T
authors.initials: SG
authors.lastname: Devaraj
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Sun
authors.affiliation: Beta Cat Pharmaceutical, Gaithersburg, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Horrigan
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Leveque
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zu
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Iyer
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: Bhalla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D051176:beta Catenin; D006655:Histone Deacetylases