panobinostat and Blast-Crisis

Present studies show that LBH589, a novel cinnamic hydroxamic acid analog histone deacetylase inhibitor, induces acetylation of histone H3 and H4 and of heat shock protein 90 (hsp90), increases p21 levels, as well as induces cell-cycle G(1) phase accumulation and apoptosis of the human chronic myeloid leukemia blast crisis (CML-BC) K562 cells and acute leukemia MV4-11 cells with the activating length mutation of FLT-3. In MV4-11 cells, this was associated with marked attenuation of the protein levels of p-FLT-3, FLT-3, p-AKT, and p-ERK1/2. In K562 cells, exposure to LBH589 attenuated Bcr-Abl, p-AKT, and p-ERK1/2. Treatment with LBH589 inhibited the DNA binding activity of signal transducers and activators of transcription 5 (STAT5) in both K562 and MV4-11 cells. The hsp90 inhibitor 17-allyl-amino-demethoxy geldanamycin (17-AAG) also induced polyubiquitylation and proteasomal degradation of FLT-3 and Bcr-Abl by reducing their chaperone association with hsp90. Cotreatment with LBH589 and 17-AAG exerted synergistic apoptosis of MV4-11 and K562 cells. In the imatinib mesylate (IM)-refractory leukemia cells expressing Bcr-Abl with the T315I mutation, treatment with the combination attenuated the levels of the mutant Bcr-Abl and induced apoptosis. Finally, cotreatment with LBH589 and 17-AAG also induced more apoptosis of IM-resistant primary CML-BC and acute myeloid leukemia (AML) cells (with activating mutation of FLT-3) than treatment with either agent alone.

Topics: Acute Disease; Apoptosis; Benzamides; Benzoquinones; Blast Crisis; Cell Line, Tumor; Drug Combinations; Drug Synergism; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; Fusion Proteins, bcr-abl; Gene Deletion; Gene Expression Regulation; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Hydroxamic Acids; Imatinib Mesylate; Indoles; K562 Cells; Lactams, Macrocyclic; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Panobinostat; Piperazines; Point Mutation; Polyubiquitin; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins; Pyrimidines; Receptor Protein-Tyrosine Kinases; Rifabutin