title: Small-molecule inhibitors of the cystic fibrosis transmembrane conductance regulator increase pancreatic endocrine cell development in rat and mouse.
abstract: OBJECTIVE
  The main objective of this work was to discover new drugs that can activate the differentiation of multipotent pancreatic progenitors into endocrine cells.
  
  
  METHODS
  In vitro experiments were performed using fetal pancreatic explants from rats and mice. In this assay, we examined the actions on pancreatic cell development of glibenclamide, a sulfonylurea derivative, and glycine hydrazide (GlyH-101), a small-molecule inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR). We next tested the actions of GlyH-101 on in vivo pancreatic cell development.
  
  
  RESULTS
  Glibenclamide (10 nmol/l-100 μmol/l) did not alter the morphology or growth of the developing pancreas and exerted no deleterious effects on exocrine cell development in the pancreas. Unexpectedly, glibenclamide at its highest concentration promoted endocrine differentiation. This glibenclamide-induced promotion of the endocrine pathway could not be reproduced when other sulfonylureas were used, suggesting that glibenclamide had an off-target action. This high concentration of glibenclamide had previously been reported to inhibit CFTR. We found that the effects of glibenclamide on the developing pancreas could be mimicked both in vitro and in vivo by GlyH-101.
  
  
  CONCLUSIONS
  Collectively, we demonstrate that two small-molecule inhibitors of the CFTR, glibenclamide and GlyH-101, increase the number of pancreatic endocrine cells by increasing the size of the pool of neurogenin 3-positive endocrine progenitors in the developing pancreas.
authors.affiliation: INSERM U845, Research Center Growth and Signalling, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Faculty Necker, 156 Rue de Vaugirard, Paris, France. samia.zertal@gmail.com
authors.forename: S
authors.initials: S
authors.lastname: Zertal-Zidani
authors.forename: K
authors.initials: K
authors.lastname: Busiah
authors.forename: A
authors.initials: A
authors.lastname: Edelman
authors.forename: M
authors.initials: M
authors.lastname: Polak
authors.forename: R
authors.initials: R
authors.lastname: Scharfmann
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology*; D007120:Immunochemistry; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005905:Glyburide; D005998:Glycine; D006834:Hydrazines; D009419:Nerve Tissue Proteins; C548779:N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide; C407737:Neurog3 protein, mouse; C498696:Neurog3 protein, rat