Flavone as PARP-1 inhibitor: its effect on lipopolysaccharide induced gene-expression.
The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) which was initially known for its role in the repair of oxidative stress-induced DNA damage, has also been reported to play a mediating role in the inflammatory response. Studies with PARP-1 knockout models have shown that PARP-1 is a co-activator of Nuclear Factor-kappa B (NF-kappaB), although this appears not to require its enzyme activity. In addition, drug-induced inhibition of the enzyme activity of PARP-1 was observed to reduce the production of pro-inflammatory mediators. In this study, the flavonoid compound flavone was demonstrated to significantly inhibit the enzyme activity of PARP-1. Further evaluation of flavone in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-treated human pulmonary epithelial and vascular endothelial cells revealed that both the decrease in NAD(+) levels, as well as the formation of PAR-polymers was dose-dependently attenuated by flavone. In addition, flavone was found to reduce the lipopolysaccharide (LPS)-induced interleukin (IL)-8 production in pulmonary epithelial cells, which was confirmed by transcription analysis. Furthermore, the transcription Inhibitor kappa B alpha (of IkappaBalpha) was significantly increased by flavone. The results of the present study indicate that the flavonoid flavone could be a potential candidate for application in treatment of chronic inflammatory diseases. PARP-1 inhibition could have beneficial effects in such diseases as Chronic Obstructive Pulmonary Disease (COPD) and diabetes, by preservation of cellular NAD(+) levels and attenuating inflammatory conditions.
Geraets
Liesbeth
L
Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands. l.geraets@farmaco.unimaas.nl
Moonen
Harald J J
HJ
Brauers
Karen
K
Gottschalk
Ralph W H
RW
Wouters
Emiel F M
EF
Bast
Aalt
A
Hageman
Geja J
GJ
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005296:Ferrous Compounds / Q000378:metabolism / Q000494:pharmacology; D047309:Flavones; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D015394:Molecular Structure; D009243:NAD / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009708:Nucleotidases / Q000494:pharmacology; D010616:Phenanthrenes / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019097:Spin Trapping / Q000379:methods; D014158:Transcription, Genetic / Q000187:drug effects
D000975:Antioxidants; D001549:Benzamides; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D005296:Ferrous Compounds; D047309:Flavones; D005419:Flavonoids; D016209:Interleukin-8; D008070:Lipopolysaccharides; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D016328:NF-kappa B; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; D008769:Methylnitronitrosoguanidine; C020748:ferrous sulfate; C069977:2,2-dimethyl-5-hydroxy-1-pyrrolidinyloxy; C025160:3-aminobenzamide; D006861:Hydrogen Peroxide; D000429:Alcohol Oxidoreductases; C110191:phenylacetaldehyde reductase; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C021896:2'-nucleotidase; D009708:Nucleotidases; C043562:flavone