title: A cystic fibrosis respiratory epithelial cell chronically treated by miglustat acquires a non-cystic fibrosis-like phenotype.
abstract: Cystic fibrosis (CF) is a fatal, autosomal and recessive genetic disease that is mainly due to inactivating mutations in the chloride channel CF transmembrane conductance regulator (CFTR). Sodium hyperabsorption by the airways, profound lung inflammation, and dysregulation of calcium homeostasis, are presumably causally related to loss of CFTR-dependent chloride function in patients with CF. Miglustat (N-butyldeoxynojirimycin, Zavesca), an inhibitor of the alpha-1,2 glucosidase, has been proposed for clinical use in CF because of its effect as a corrector of the defective trafficking of F508del-CFTR. In the present study, we show that daily treatment for 2 months with low concentrations of miglustat on the human CF nasal epithelial cell line, JME/CF15 (F508del/F508del-CFTR), results in progressive, stable, reversible, and sustained correction of F508del-CFTR trafficking, down-regulation of sodium hyperabsorption, and regulation of the calcium homeostasis. In conclusion, we provide here the first evidence that a respiratory CF cell can acquire a non-CF-like phenotype when chronically treated with low concentrations of a pharmacological drug.
authors.affiliation: IPBC, Université de Poitiers, 40 Avenue du Recteur Pineau, 86022 Poitiers, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Norez
authors.forename: Fabrice
authors.initials: F
authors.lastname: Antigny
authors.forename: Sabrina
authors.initials: S
authors.lastname: Noel
authors.forename: Clarisse
authors.initials: C
authors.lastname: Vandebrouck
authors.forename: Frédéric
authors.initials: F
authors.lastname: Becq
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051379:Mice; D018408:Patch-Clamp Techniques; D010641:Phenotype; D020545:Respiratory Mucosa / Q000166:cytology*
chemical_list: D004791:Enzyme Inhibitors; D053503:Epithelial Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017485:1-Deoxynojirimycin; C059896:miglustat; D002118:Calcium