Inhibition of nuclear factor-kappaB by a nitro-derivative of flurbiprofen: a possible mechanism for antiinflammatory and antiproliferative effect.
Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used in the treatment of chronic inflammatory states. In addition, they show promise for the prevention and therapy of colon cancers and of Alzheimer's disease, although their gastrointestinal toxicity is of concern for these indications. Nitric oxide-releasing NSAIDs are reported to be safer than their parent compounds. We report here that flurbiprofen nitroxybutyl ester inhibits nuclear factor-kappaB (NF-kappaB) activity and cell growth in L929 cells at a concentration of 100 microM, whereas flurbiprofen is inactive. Inhibition of cell growth is not due to the induction of apoptosis, but to a retardation of all phases of the cell cycle. NF-kappaB is implicated both in the control of immune and inflammatory response and in the control of cell proliferation and apoptosis. Therefore, its inhibition at low concentrations by an NSAID with low gastrointestinal toxicity could be important for all the above-mentioned therapeutic indications.
Fratelli
Maddalena
M
Mario Negri Institute of Pharmacological Research, Via Eritrea 62, I-20157 Milan, Italy. maddalena@marionegri.it
Minto
Manuela
M
Crespi
Andrea
A
Erba
Eugenio
E
Vandenabeele
Peter
P
Del Soldato
Piero
P
Ghezzi
Pietro
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017930:Genes, Reporter; D007249:Inflammation / Q000188:drug therapy; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000378:metabolism; D013997:Time Factors
C478649:2-fluoro-alpha-methyl-(1,1'-biphenyl)-4-acetic acid 4-(nitro-oxy)butyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D009569:Nitric Oxide; D005480:Flurbiprofen; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase