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
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.