Suppression of tumor necrosis factor-activated nuclear transcription factor-κB, activator protein-1, c-Jun N-terminal kinase, and apoptosis by β-lapachone

beta-Lapachone, the product of a tree from South America, is known to exhibit various pharmacologic properties, the mechanisms of which are poorly understood. In the present report, we examined the effect of beta-lapachone on the tumor necrosis factor (TNF)-induced activation of the nuclear transcription factors NF-kappa B and activator protein-1 (AP-1) in human myeloid U937 cells. TNF-induced NF-kappa B activation, p65 translocation, I kappa B alpha degradation, and NF-kappa B-dependent reporter gene expression were inhibited in cells pretreated with beta-lapachone. Direct treatment of the p50-p65 heterodimer of NF-kappa B with beta-lapachone had no effect on its ability to bind to the DNA. Besides myeloid cells, beta-lapachone was also inhibitory in T-cells and epithelial cells. beta-Lapachone also suppressed the activation of NF-kappa B by lipopolysaccharide, okadaic acid, and ceramide but had no significant effect on activation by H2O2 or phorbol myristate acetate, indicating that its action is selective. beta-Lapachone also abolished TNF-induced activation of AP-1, c-Jun N-terminal kinase, and mitogen-activated protein kinase kinase (MAPKK or MEK). TNF-induced cytotoxicity and activation of caspase-3 were also abolished by beta-lapachone. Because reducing agents (dithiothreitol and N-acetylcysteine) reversed the effect of beta-lapachone, it suggests the role of a critical sulfhydryl group. Overall, our results identify NF-kappa B, AP-1, and apoptosis as novel targets for beta-lapachone, and this may explain some of its pharmacologic effects. (C) 1999 Elsevier Science Inc.