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Histone deacetylase inhibitor NVP-LAQ824 has significant activity against myeloid leukemia cells in vitro and in vivo

Leukemia volume 18, pages 1951–1963 (2004)Cite this article

Abstract

NVP-LAQ824 is a novel potent hydroxamic acid-derived histone deacetylase inhibitor that induces apoptosis in nanomolar concentrations in myeloid leukemia cell lines and patient samples. Here we show the activity of NVP-LAQ824 in acute myeloid leukemia cells and BCR/ABL-expressing cells of mouse and human origin, both sensitive and resistant to imatinib mesylate (Gleevec, STI-571). Whereas imatinib inhibited overall cellular tyrosine phosphorylation in Ba/F3.p210 cells, NVP-LAQ824 did not inhibit tyrosine phosphorylation, and did not affect BCR/ABL or ABL protein expression. Neither compound was able to inhibit cellular tyrosine phosphorylation in the imatinib-resistant Ba/F3.p210-T315I cell line. These data taken together suggest that BCR/ABL kinase activity is not a direct target of NVP-LAQ824. Synergy between NVP-LAQ824 and imatinib was demonstrated against BCR/ABL-expressing K562 myeloid leukemia cell lines. In addition, we show that NVP-LAQ824 was well tolerated in vivo in a pre-clinical murine leukemia model, with antileukemia activity resulting in significant prolongation of the survival of mice when treated with NVP-LAQ824 compared to control mice. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in myeloid malignancies.

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Acknowledgements

This work was carried out at the Dana-Farber Cancer Institute, Boston, MA and supported by the National Institutes of Health grants ROI50947 and POI78378, and the Doris Duke Distinguished Clinical Research Scientist Award (KCA).

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Author notes

  1. E Weisberg and L Catley: These authors contributed equally to this work

  2. P Atadja and S Remiszewski: Employed by a company (Novartis) whose product imatinib and (potential) product NVP-LAQ824 were studied in the present work

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

    E Weisberg, L Catley, J Kujawa, C Cavazza, K Anderson & J D Griffin

  2. Department of Medicine, Harvard Medical School, Boston, MA, USA

    E Weisberg, L Catley, J Kujawa, C Cavazza, K Anderson & J D Griffin

  3. Novartis Institutes for Biomedical Research, Oncology Research, East Hanover, NJ, USA

    P Atadja, S Remiszewski & P Fuerst

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  1. E Weisberg
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Correspondence to L Catley.

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Materials and methods for cell culture, cell cycle, cytotoxicity assays and Western blot are listed in Supplementary Information on the Leukemia website (http://www.nature.com/leu).

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Weisberg, E., Catley, L., Kujawa, J. et al. Histone deacetylase inhibitor NVP-LAQ824 has significant activity against myeloid leukemia cells in vitro and in vivo. Leukemia 18, 1951–1963 (2004). https://doi.org/10.1038/sj.leu.2403519

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