laq824 and Leukemia--Myeloid

Topics: Acetylation; Acute Disease; Animals; Antineoplastic Agents; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Leukemia, Myeloid

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.

Topics: Acetylation; Acute Disease; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Bone Marrow Cells; Cell Cycle; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Inhibitors; Female; Fusion Proteins, bcr-abl; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Imatinib Mesylate; In Vitro Techniques; Leukemia, Myeloid; Mice; Mice, Inbred BALB C; Phosphorylation; Piperazines; Pyrimidines; Tumor Cells, Cultured; Tyrosine