Novel Action of the Chalcone Isoliquiritigenin as a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Inhibitor: Potential Therapy for Cholera and Polycystic Kidney Disease

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 IC50 of approximately 20 mu M. ISLQ had no effect on either basal short-circuit current or Ca2+-activated Cl- secretion. Apical 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.