title: The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide.
abstract: Determinants of differentiation and apoptosis induction by the novel histone deacetylase inhibitor (HDACI) LAQ824 were examined in human leukemia cells (U937 and Jurkat). Exposure of U937 cells to a low concentration of LAQ824 (30 nM) resulted in a delayed (2 h) increase in reactive oxygen species (ROS), induction of p21(WAF1/CIP1), pRb dephosphorylation, growth arrest of cells in G(0)/G(1) phase, and differentiation. On the other hand, exposure of cells to a higher concentration of LAQ824 (75 nM) resulted in the early (30 min) generation of ROS, arrest of cells in G(2)/M phase, down-regulation of XIAP (at the transcriptional level) and Mcl-1 (through a caspase-mediated process), the acid sphingomyelinase-dependent generation of ceramide, and profound mitochondrial injury, caspase activation, and apoptosis. LAQ824-induced lethality in U937 cells did not involve the extrinsic apoptotic pathway, nor was it associated with death receptor up-regulation; instead, it was markedly inhibited by ectopic expression of Bcl-2, Bcl-x(L), XIAP, and Mcl-1. The free radical scavenger N-acetyl cysteine blocked LAQ824-mediated ROS generation, mitochondrial injury, Mcl-1 down-regulation, ceramide generation, and apoptosis, suggesting a primary role for oxidative injury in LAQ824 lethality. Together, these findings indicate that LAQ824-induced lethality represents a multifactorial process in which LAQ824-mediated ROS generation is necessary but not sufficient to induce apoptosis, and that the degree of XIAP and Mcl-1 down-regulation and ceramide generation determines whether this agent engages a maturation rather than an apoptotic program.
authors.affiliation: Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Roberto R
authors.initials: RR
authors.lastname: Rosato
authors.forename: Sonia C
authors.initials: SC
authors.lastname: Maggio
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Almenara
authors.forename: Shawn G
authors.initials: SG
authors.lastname: Payne
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Sarah
authors.initials: S
authors.lastname: Spiegel
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002518:Ceramides / Q000096:biosynthesis*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D019169:Jurkat Cells; D007938:Leukemia / Q000473:pathology*; D018384:Oxidative Stress; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D020298:U937 Cells; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000502:physiology*
chemical_list: D002518:Ceramides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C477361:LAQ824; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D013108:Sphingomyelin Phosphodiesterase