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

Citation
Sk. Manna et al., Suppression of tumor necrosis factor-activated nuclear transcription factor-kappa B, activator protein-1, c-Jun N-terminal kinase, and apoptosis by beta-lapachone, BIOCH PHARM, 57(7), 1999, pp. 763-774
Citations number
42
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
00062952 → ACNP
Volume
57
Issue
7
Year of publication
1999
Pages
763 - 774
Database
ISI
SICI code
0006-2952(19990401)57:7<763:SOTNFN>2.0.ZU;2-4
Abstract
beta-Lapachone, the product of a tree from South America, is known to exhib it various pharmacologic properties, the mechanisms of which are poorly und erstood. In the present report, we examined the effect of beta-lapachone on the tumor necrosis factor (TNF)-induced activation of the nuclear transcri ption factors NF-kappa B and activator protein-1 (AP-1) in human myeloid U9 37 cells. TNF-induced NF-kappa B activation, p65 translocation, I kappa B a lpha degradation, and NF-kappa B-dependent reporter gene expression were in hibited in cells pretreated with beta-lapachone. Direct treatment of the p5 0-p65 heterodimer of NF-kappa B with beta-lapachone had no effect on its ab ility to bind to the DNA. Besides myeloid cells, beta-lapachone was also in hibitory in T-cells and epithelial cells. beta-Lapachone also suppressed th e activation of NF-kappa B by lipopolysaccharide, okadaic acid, and ceramid e but had no significant effect on activation by H2O2 or phorbol myristate acetate, indicating that its action is selective. beta-Lapachone also aboli shed TNF-induced activation of AP-1, c-Jun N-terminal kinase, and mitogen-a ctivated protein kinase kinase (MAPKK or MEK). TNF-induced cytotoxicity and activation of caspase-3 were also abolished by beta-lapachone. Because red ucing agents (dithiothreitol and N-acetylcysteine) reversed the effect of b eta-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.