Cotreatment with Histone Deacetylase Inhibitor LAQ824 Enhances Apo-2L/Tumor Necrosis Factor-Related Apoptosis Inducing Ligand-Induced Death Inducing Signaling Complex Activity and Apoptosis of Human Acute Leukemia Cells

摘要: Present studies demonstrate that treatment with the histone deacetylases inhibitor LAQ824, a cinnamic acid hydroxamate, increased acetylation of histones H3 and H4, as well induced p21 WAF1 in human T-cell acute leukemia Jurkat, B lymphoblast SKW 6.4, myelogenous HL-60 cells. This was associated accumulation cells G 1 phase cell cycle, accompanied by processing activity caspase-9 -3, apoptosis. Exposure to LAQ824 mRNA protein expressions death receptors DR5 and/or DR4, but reduced levels cellular FLICE-inhibitory (c-FLIP). As compared Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or alone, pretreatment assembly Fas-associated domain caspase-8, not c-FLIP, into Apo-2L/TRAIL-induced death-inducing signaling complex. caspase-8 Bcl-2 interacting (BID), augmented cytosolic prodeath molecules cytochrome-c, Smac Omi, led caspase-3 Treatment also down-regulated Bcl-2, Bcl-x L , XIAP, survivin. Partial inhibition apoptosis due Apo-2L/TRAIL exerted overexpression reversed cotreatment Apo-2L/TRAIL. Significantly, primary blast samples isolated from 10 patients leukemia. Taken together, these findings indicate may have promising augmenting complex