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Received for publication July 26, 2005.
Revised September 27, 2005.
Accepted for publication September 27, 2005.
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 hr) increase in ROS, induction of p21WAF1/CIP1, pRb dephosphorylation, growth arrest of cells in G0/G1, 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 G2/M, 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 upregulation; instead, it was markedly inhibited by ectopic expression of Bcl-2, Bcl-xL, XIAP and Mcl-1. The free radical scavenger N-acetyl cysteine (NAC) 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 as well as ceramide generation determines whether this agent engages a maturation rather than an apoptotic program.
Key words:
Apoptosis, Oxidative stress/antioxidants, Mechanisms of cell killing/apoptosis
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