title: Identification of a novel blocker of IkappaBalpha kinase activation that enhances apoptosis and inhibits proliferation and invasion by suppressing nuclear factor-kappaB.
abstract: 3,4-dihydroxybenzalacetone (DBL) is a polyphenol derived from the medicinal plant Chaga [Inonotus obliquus (persoon) Pilat]. Although Chaga is used in Russia folk medicine to treat tumors, very little is known about its mechanism of action. Because most genes involved in inflammation, antiapoptosis, and cell proliferation are regulated by the transcription factor nuclear factor-kappaB (NF-kappaB), we postulated that DBL activity is mediated via modulation of the NF-kappaB activation pathway. We investigated the effects of DBL on NF-kappaB activation by electrophoretic mobility shift assay and on NF-kappaB-regulated gene expression by Western blot analysis. We found that DBL suppressed NF-kappaB activation by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1beta, epidermal growth factor, okadaic acid, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific and inhibited both inducible and constitutive NF-kappaB activation. DBL did not interfere with the binding of NF-kappaB to DNA but rather inhibited IkappaBalpha kinase activity, IkappaBalpha phosphorylation and degradation, p65 phosphorylation, and translocation. DBL also suppressed the expression of TNF-induced and NF-kappaB-regulated proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of TNF-induced apoptosis and suppression of TNF-induced invasion. Together, our results indicate that DBL inhibits NF-kappaB activation and NF-kappaB-regulated gene expression, which may explain the ability of DBL to enhance apoptosis and inhibit invasion.
authors.affiliation: Cytokine Research Section, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Unit 143, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Bokyung
authors.initials: B
authors.lastname: Sung
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Pandey
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishida
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Konishi
authors.forename: Madan M
authors.initials: MM
authors.lastname: Chaturvedi
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D059808:Polyphenols; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D016328:NF-kappa B; D010636:Phenols; D059808:Polyphenols; D047428:Protein Kinase Inhibitors; D048069:Tumor Necrosis Factors; D004247:DNA; D051550:I-kappa B Kinase