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Suppression of tumor necrosis factor-activated nuclear transcription factor-kappaB, activator protein-1, c-Jun N-terminal kinase, and apoptosis by beta-lapachone.
Biochem Pharmacol. 1999 Apr 01; 57(7):763-74.BP

Abstract

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.

Authors+Show Affiliations

Department of Molecular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10075082

Citation

Manna, S K., et al. "Suppression of Tumor Necrosis Factor-activated Nuclear Transcription factor-kappaB, Activator Protein-1, c-Jun N-terminal Kinase, and Apoptosis By Beta-lapachone." Biochemical Pharmacology, vol. 57, no. 7, 1999, pp. 763-74.
Manna SK, Gad YP, Mukhopadhyay A, et al. Suppression of tumor necrosis factor-activated nuclear transcription factor-kappaB, activator protein-1, c-Jun N-terminal kinase, and apoptosis by beta-lapachone. Biochem Pharmacol. 1999;57(7):763-74.
Manna, S. K., Gad, Y. P., Mukhopadhyay, A., & Aggarwal, B. B. (1999). Suppression of tumor necrosis factor-activated nuclear transcription factor-kappaB, activator protein-1, c-Jun N-terminal kinase, and apoptosis by beta-lapachone. Biochemical Pharmacology, 57(7), 763-74.
Manna SK, et al. Suppression of Tumor Necrosis Factor-activated Nuclear Transcription factor-kappaB, Activator Protein-1, c-Jun N-terminal Kinase, and Apoptosis By Beta-lapachone. Biochem Pharmacol. 1999 Apr 1;57(7):763-74. PubMed PMID: 10075082.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suppression of tumor necrosis factor-activated nuclear transcription factor-kappaB, activator protein-1, c-Jun N-terminal kinase, and apoptosis by beta-lapachone. AU - Manna,S K, AU - Gad,Y P, AU - Mukhopadhyay,A, AU - Aggarwal,B B, PY - 1999/3/13/pubmed PY - 1999/3/13/medline PY - 1999/3/13/entrez SP - 763 EP - 74 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 57 IS - 7 N2 - 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. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/10075082/Suppression_of_tumor_necrosis_factor_activated_nuclear_transcription_factor_kappaB_activator_protein_1_c_Jun_N_terminal_kinase_and_apoptosis_by_beta_lapachone_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(98)00354-2 DB - PRIME DP - Unbound Medicine ER -