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Acute Leukemias

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

Leukemia volume 29, pages 1267–1278 (2015)Cite this article

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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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Acknowledgements

This work was supported by a grant from the National Institutes of Health, National Cancer Institute (R01 CA173877) (K.N.B.).

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Authors and Affiliations

  1. Houston Methodist Research Institute, Houston, TX, USA

    W Fiskus, S Saha, B Shah, S G T Devaraj, B Sun, C Leveque, Y Zu, S Iyer & K N Bhalla

  2. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    S Sharma

  3. Beta Cat Pharmaceutical, Gaithersburg, MD, USA

    S Horrigan

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Correspondence to K N Bhalla.

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Stephan Horrigan is Chief Scientific Officer of β-Cat Pharma, Inc. The remaining authors declare no conflict of interest.

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Fiskus, W., Sharma, S., Saha, S. et al. Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells. Leukemia 29, 1267–1278 (2015). https://doi.org/10.1038/leu.2014.340

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