Gene interactions and pathways from curated databases and text-mining
Biochem Pharmacol 1999, PMID: 10075082

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

Manna, S K; Gad, Y P; Mukhopadhyay, A; Aggarwal, B B

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-kappaB and activator protein-1 (AP-1) in human myeloid U937 cells. TNF-induced NF-kappaB activation, p65 translocation, IkappaBalpha degradation, and NF-kappaB-dependent reporter gene expression were inhibited in cells pretreated with beta-lapachone. Direct treatment of the p50-p65 heterodimer of NF-kappaB 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-kappaB 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-kappaB, AP-1, and apoptosis as novel targets for beta-lapachone, and this may explain some of its pharmacologic effects.

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Text Mining Data

transcription factor-kappaB → tumor necrosis factor: " Suppression of tumor necrosis factor activated nuclear transcription factor-kappaB , activator protein-1, c-Jun N-terminal kinase, and apoptosis by beta-lapachone "

activator protein-1 → tumor necrosis factor: " Suppression of tumor necrosis factor activated nuclear transcription factor-kappaB, activator protein-1 , c-Jun N-terminal kinase, and apoptosis by beta-lapachone "

p65 → TNF: " TNF induced NF-kappaB activation, p65 translocation, IkappaBalpha degradation, and NF-kappaB dependent reporter gene expression were inhibited in cells pretreated with beta-lapachone "

NF-kappaB → TNF: " TNF induced NF-kappaB activation, p65 translocation, IkappaBalpha degradation, and NF-kappaB dependent reporter gene expression were inhibited in cells pretreated with beta-lapachone "

IkappaBalpha → TNF: " TNF induced NF-kappaB activation, p65 translocation, IkappaBalpha degradation, and NF-kappaB dependent reporter gene expression were inhibited in cells pretreated with beta-lapachone "

AP-1 → TNF: " Beta-lapachone also abolished TNF induced activation of AP-1 , c-Jun N-terminal kinase, and mitogen activated protein kinase kinase ( MAPKK or MEK ) "

mitogen activated protein kinase kinase → TNF: " Beta-lapachone also abolished TNF induced activation of AP-1, c-Jun N-terminal kinase, and mitogen activated protein kinase kinase ( MAPKK or MEK ) "

caspase-3 → TNF: " TNF induced cytotoxicity and activation of caspase-3 were also abolished by beta-lapachone "

Manually curated Databases

No curated data.