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 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 campdependent 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. © the japanese pharmacological society.