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

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.

• Authors: E Weisberg, L Catley, J Kujawa, P Atadja, S Remiszewski, P Fuerst, C Cavazza, K Anderson, J D Griffin
• Journal: Leukemia (Leukemia) Vol. 18 Issue 12 Pg. 1951-63 (Dec 2004) ISSN: 0887-6924 [Print] England
• PMID: 15496979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzamides
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• LAQ824
• Piperazines
• Pyrimidines
• Tyrosine
• Imatinib Mesylate
• Fusion Proteins, bcr-abl

Topics

• Acetylation
• Acute Disease
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Benzamides
• Bone Marrow Cells (drug effects, metabolism, pathology)
• Cell Cycle (drug effects)
• Drug Resistance, Neoplasm
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• Female
• Fusion Proteins, bcr-abl (metabolism)
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (administration & dosage)
• Imatinib Mesylate
• In Vitro Techniques
• Leukemia, Myeloid (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Phosphorylation (drug effects)
• Piperazines (administration & dosage)
• Pyrimidines (administration & dosage)
• Tumor Cells, Cultured
• Tyrosine (metabolism)