title: Calagualine inhibits nuclear transcription factors-kappaB activated by various inflammatory and tumor promoting agents.
abstract: Calagualine derived from the fern of the genus Polypodium, commonly called calaguala, has had clinically documented medicinal uses in South America and Spain and been shown to block tumor metastasis, proliferation, and inflammation, all known to require the activation of nuclear transcription factor-kappaB (NF-kappaB). Therefore, we investigated the effect of calagualine on NF-kappaB activation induced by various inflammatory and tumor promoting agents. Calagualine blocked tumor necrosis factor (TNF)-induced activation of NF-kappaB through inhibition of phosphorylation and degradation of IkappaBalpha, an inhibitor of NF-kappaB. The effects of calagualine were not cell type-specific, as it blocked TNF-induced NF-kappaB activation in a variety of cells. NF-kappaB-dependent reporter gene transcription activated by TNF was also suppressed by calagualine. The TNF-induced NF-kappaB activation cascade involving TNFR1-TNF receptor-associated death domain-TNF receptor-associated factor 2 (TRAF2)-NF-kappaB-inducing kinase (NIK)-IkappaBalpha kinase was interrupted at the TRAF2 and NIK sites by calagualine, which would account for its suppression of NF-kappaB reporter gene expression. Calagualine blocked NF-kappaB activation induced by phorbol ester and lipopolysaccharide. Overall our results indicate that calagualine inhibits activation of NF-kappaB and this may provide a molecular basis for calagualine's ability to suppress inflammation and tumorigenesis.
authors.affiliation: Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 143, Houston, TX 77030, USA
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Manna
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueso-Ramos
authors.forename: Francisco
authors.initials: F
authors.lastname: Alvarado
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: D002518:Ceramides / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D006027:Glycosides / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D002518:Ceramides; D006027:Glycosides; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010703:Phorbol Esters; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D019319:Okadaic Acid; C006870:anapsos