title: Novel action of the chalcone isoliquiritigenin as a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor: potential therapy for cholera and polycystic kidney disease.
abstract: Overstimulation of cAMP-activated Cl(-) secretion can cause secretory diarrhea. Isoliquiritigenin (ISLQ) is a plant-derived chalcone that has a wide range of biological activities. The present study thus aimed to investigate the effect of ISLQ on cAMP-activated Cl(-) secretion in human intestinal epithelium, especially the underlying mechanism and therapeutic application. Short-circuit current analysis of human intestinal epithelial (T84) cell monolayers revealed that ISLQ dose-dependently inhibited cAMP-activated Cl(-) secretion with an IC(50) of approximately 20 µM. ISLQ had no effect on either basal short-circuit current or Ca(2+)-activated Cl(-) secretion. Apical Cl(-) current analysis of T84 cell monolayers indicated that ISLQ blocked mainly the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels, but not other unidentified cAMP-dependent Cl(-) channels. ISLQ did not affect intracellular cAMP levels or cell viability. ISLQ completely abolished the cholera toxin-induced transepithelial Cl(-) secretion in T84 cells and reduced the cholera toxin-induced intestinal fluid secretion in mouse closed loop models by 90%. Similarly, ISLQ completely inhibited the cAMP-activated apical Cl(-) current across monolayers of Madin-Darby Canine Kidney (MDCK) cells and retarded cyst growth in MDCK cyst models by 90%. This study reveals a novel action of ISLQ as a potent CFTR inhibitor with therapeutic potential for treatment of cholera and polycystic kidney disease.
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Thailand. scchatchai@mahidol.ac.th
authors.forename: Chatchai
authors.initials: C
authors.lastname: Muanprasat
authors.forename: Lalida
authors.initials: L
authors.lastname: Sirianant
authors.forename: Sunhapas
authors.initials: S
authors.lastname: Soodvilai
authors.forename: Ratchanaporn
authors.initials: R
authors.lastname: Chokchaisiri
authors.forename: Apichart
authors.initials: A
authors.lastname: Suksamrarn
authors.forename: Varanuj
authors.initials: V
authors.lastname: Chatsudthipong
mesh_terms: D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology*; D002460:Cell Line; D047188:Chalcones / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism; D002771:Cholera; D002772:Cholera Toxin / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors*; D004285:Dogs; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D007690:Polycystic Kidney Diseases
chemical_list: D000930:Antidiarrheals; D047188:Chalcones; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002772:Cholera Toxin; C040920:isoliquiritigenin