RRC ID 43052
Author Geraets L, Moonen HJ, Brauers K, Gottschalk RW, Wouters EF, Bast A, Hageman GJ.
Title Flavone as PARP-1 inhibitor: its effect on lipopolysaccharide induced gene-expression.
Journal Eur J Pharmacol
Abstract 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.
Volume 573(1-3)
Pages 241-8
Published 2007-11-14
DOI 10.1016/j.ejphar.2007.07.013
PII S0014-2999(07)00794-7
PMID 17643414
MeSH Alcohol Oxidoreductases / antagonists & inhibitors Alcohol Oxidoreductases / metabolism Antioxidants / chemistry Antioxidants / metabolism Benzamides / pharmacology Cell Line, Tumor Cell Nucleus / drug effects Cell Nucleus / metabolism Cyclic N-Oxides / metabolism Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Ferrous Compounds / metabolism Ferrous Compounds / pharmacology Flavones Flavonoids / chemistry Flavonoids / pharmacology* Gene Expression Regulation / drug effects* Humans Hydrogen Peroxide / metabolism Hydrogen Peroxide / pharmacology Interleukin-8 / genetics Interleukin-8 / metabolism Lipopolysaccharides / pharmacology* Methylnitronitrosoguanidine / pharmacology Molecular Structure NAD / metabolism NF-kappa B / genetics NF-kappa B / metabolism Nucleotidases / pharmacology Phenanthrenes / pharmacology Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerase Inhibitors* Poly(ADP-ribose) Polymerases / metabolism Reverse Transcriptase Polymerase Chain Reaction Spin Trapping / methods Transcription, Genetic / drug effects
IF 3.17
Times Cited 18
Human and Animal Cells