Arsenic trioxide represses constitutive activation of NF-κB and COX-2 expression in human acute myeloid leukemia, HL-60

It has been proposed that eukaryotic nuclear transcripton factor nuclear factor kappa-B (NF-kappaB) and cyclooxygenase-2 (COX-2) are implicated in the pathogenesis of many human diseases including cancer. Arsenic has been widely used in medicine in Oriental countries. Recent studies have shown that arsenic trioxide (AS(2)O(3)) Could induce in vitro growth inhibition and apoptosis of malignant lymphocytes, and myeloma cells. However, the molecular mechanisms by which AS(2)O(3) initiates cellular signaling toward cell death are still unclear. In the present study, the effects of AS(2)O(3) on NF-kappaB and COX-2 expression in HL-60 cells were investigated. AS(2)O(3) suppressed DNA-binding activity of NF-kappaB composed of p65/p50 heterodimer through preventing the degradation of IkappaB-alpha and the nuclear translocation of p65 subsequently as well as interrupting the binding of NF-kappaB with their consensus sequences. Inhibitory effect of AS(2)O(3) on NF-kappaB DNA activity was dependent upon intracellular glutathione (GSH) and H2O2 level, but not superoxide anion. Furthermore, we found that AS(2)O(3) also downregulated the expression of COX-2, which has NF-kappaB binding site on its promoter through repressing the NF-kappaB DNA-binding activity. (C) 2004 Wiley-Liss, Inc.