title: Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking.
abstract: BACKGROUND
  Small molecules as shown by VX809 can rescue the mislocalization of F508del-CFTR. The aim of this study was to identify correctors with a clinical history and their targets of action.
  
  
  METHODS
  CFTR correctors were screened using two F508del-CFTR expressing cell based HTS assays. Electrophysiological studies using CFBE41o(-) and HBE cells and in-vivo mouse assays confirmed CFTR rescue. The target of action was attained using pharmacological inhibitors and siRNA to specific genes.
  
  
  RESULTS
  Ibuprofen was identified as a CFTR corrector. Ibuprofen treatment of polarized CFBE41o(-) monolayers increased the short-circuit current (Isc) response to stimulation. In vivo CF mice treatment with ibuprofen restored the CFTR trafficking. SiRNA knock down of cyclooxygenase expression caused partial F508del-CFTR correction.
  
  
  CONCLUSIONS
  These studies show that ibuprofen is a CFTR corrector and that it causes correction by COX-1 inhibition. Hence ibuprofen may be suitable to be part of a future CF combination therapy.
authors: Cystic Fibrosis Translational Research Center, Dept. of Biochemistry, McGill University, Montreal, Quebec H3G1Y6, Canada. Electronic address: graeme.carlile@mcgill.ca.
authors: Graeme W
authors: GW
authors: Carlile
authors: Cystic Fibrosis Translational Research Center, Dept. of Physiology, McGill University, Montreal, Quebec H3G1Y6, Canada.
authors: Renaud
authors: R
authors: Robert
authors: Cystic Fibrosis Translational Research Center, Dept. of Physiology, McGill University, Montreal, Quebec H3G1Y6, Canada.
authors: Julie
authors: J
authors: Goepp
authors: Cystic Fibrosis Translational Research Center, Dept. of Physiology, McGill University, Montreal, Quebec H3G1Y6, Canada.
authors: Elizabeth
authors: E
authors: Matthes
authors: Cystic Fibrosis Translational Research Center, Dept. of Physiology, McGill University, Montreal, Quebec H3G1Y6, Canada.
authors: Jie
authors: J
authors: Liao
authors: Hospital for Sick Children, Dept. of Biochemistry, University of Toronto, Ontario M5G 1X8, Canada.
authors: Bart
authors: B
authors: Kus
authors: Cystic Fibrosis Translational Research Center, Dept. of Biochemistry, McGill University, Montreal, Quebec H3G1Y6, Canada.
authors: Sean D
authors: SD
authors: Macknight
authors: Hospital for Sick Children, Dept. of Biochemistry, University of Toronto, Ontario M5G 1X8, Canada.
authors: Daniela
authors: D
authors: Rotin
authors: Cystic Fibrosis Translational Research Center, Dept. of Physiology, McGill University, Montreal, Quebec H3G1Y6, Canada.
authors: John W
authors: JW
authors: Hanrahan
authors: Cystic Fibrosis Translational Research Center, Dept. of Biochemistry, McGill University, Montreal, Quebec H3G1Y6, Canada.
authors: David Y
authors: DY
authors: Thomas
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D051379:Mice; D018181:Mice, Inbred CFTR; D009154:Mutation; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D016861:Cyclooxygenase Inhibitors; D034741:RNA, Small Interfering; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D007052:Ibuprofen
keywords: Cystic fibrosis; NSAID; Protein folding; Protein trafficking