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A Study on Mechanism and Potential Application of Novel Chalconoid Derivatives as Anti‐Secretory Therapy for Diarrheal Diseases
Author(s) -
Yibcharoenporn Chamnan,
Chavasiri Warinthorn,
Chatsudthipong Varanuj,
Muanprasat Chatchai
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.703.16
Subject(s) - cystic fibrosis transmembrane conductance regulator , chemistry , secretion , apical membrane , chloride channel , potency , pharmacology , biochemistry , microbiology and biotechnology , biology , in vitro , membrane , gene
Secretory diarrhea is one of major health problems that mainly results from Cl − secretion through apical Cl − channels including cystic fibrosis transmembrane regulator (CFTR) and calcium‐activated chloride channel (CaCC). Naturally derived chalcone (isoliquiritigenin or ISLQ) has previously been shown to inhibit CFTR with IC 50 of about 20 μM without affecting CaCC. The aims of this study were to optimize chalconoid derivatives for their inhibitory effect against both CFTR and CaCC, and to explore their underlying mechanisms. The screening of chalconoid derivatives using short‐circuit measurements in T84 cells, a human intestinal epithelial cell line, identified an chalcone derivative CHAL‐025 that inhibited both CFTR and CaCC with higher potency than ISLQ (IC 50 for CFTR 1–5 μM and IC 50 for CaCC 3–10 μM). CHAL‐025 at concentrations up to 20 μM showed no cytotoxic effect on T84 cells. The inhibition of CFTR‐mediated chloride secretion was reversible and only observed when CHAL‐025 was added at the apical side. In addition, IC 50 of CHAL‐025 in inhibiting CFTR did not change when basolateral membrane was permeabilized, suggesting that CHAL‐025 is apically active and the inhibitory effect of CHAL‐025 is insensitive to membrane potential. CFTR inhibitory potency of CHAL‐025 was not affected by pretreatment with inhibitors of protein kinase A (PKA), protein phosphatase (PP) and phosphodiesterase (PDE), indicating that mechanisms of CFTR inhibition by CHAL‐025 did not involve PKA, PP and PDE. Mechanism of CaCC inhibition by CHAL‐025 was also investigated and will be presented. Importantly, CHAL‐025 inhibited chloride secretion induced by bile acid across T84 monolayers, which is an experimental model mimicking bile acid‐induced diarrhea. In conclusion, the present study identified a chalcone derivative that is of potential utility in the treatment of secretory diarrheas resulted from both CFTR and CaCC overstimulation. Support or Funding Information This work was supported by grants BRG5980008 and DBG5980001 from the Thailand Research Fund and Mahidol University and by the Faculty of Science, Mahidol University and the Medical Scholars Program, Mahidol University.