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Repurposing calcium-sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas
Apurva A. Oak, … , Alan S. Verkman, Onur Cil
Apurva A. Oak, … , Alan S. Verkman, Onur Cil
Published January 5, 2021
Citation Information: JCI Insight. 2021;6(4):e146823. https://doi.org/10.1172/jci.insight.146823.
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Research Article Gastroenterology Therapeutics

Repurposing calcium-sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas

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Abstract

Diarrhea is a major cause of global mortality, and outbreaks of secretory diarrhea such as cholera remain an important problem in the developing world. Current treatment of secretory diarrhea primarily involves supportive measures, such as fluid replacement. The calcium-sensing receptor (CaSR) regulates multiple biological activities in response to changes in extracellular Ca2+. The FDA-approved drug cinacalcet is an allosteric activator of CaSR used for treatment of hyperparathyroidism. Here, we found by short-circuit current measurements in human colonic T84 cells that CaSR activation by cinacalcet reduced forskolin-induced Cl– secretion by greater than 80%. Cinacalcet also reduced Cl– secretion induced by cholera toxin, heat-stable E. coli enterotoxin, and vasoactive intestinal peptide (VIP). The cinacalcet effect primarily involved indirect inhibition of cystic fibrosis transmembrane conductance regulator–mediated (CFTR-mediated) Cl– secretion following activation of CaSR and downstream phospholipase C and phosphodiesterases. In mice, cinacalcet reduced fluid accumulation by more than 60% in intestinal closed loop models of cholera and traveler’s diarrhea. The cinacalcet effect involved both inhibition of CFTR-mediated secretion and stimulation of sodium-hydrogen exchanger 3–mediated absorption. These findings support the therapeutic utility of the safe and commonly used drug cinacalcet in CFTR-dependent secretory diarrheas, including cholera, traveler’s diarrhea, and VIPoma.

Authors

Apurva A. Oak, Parth D. Chhetri, Amber A. Rivera, Alan S. Verkman, Onur Cil

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Figure 4

Cinacalcet acts from the apical side in T84 cells for inhibition of apical membrane CFTR-mediated Cl– secretion and inhibits cAMP-activated basolateral membrane K+ conductance.

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Cinacalcet acts from the apical side in T84 cells for inhibition of apic...
(A) ISC traces showing effects of 10 μM forskolin and 10 μM CFTRinh-172 with 20-minute pretreatment with 30 μM cinacalcet applied from apical, basolateral, or both sides. (B) Summary of data from experiments as in A showing Δ ISC following forskolin and CFTRinh-172. (C) ISC traces with basolateral permeabilization (amphotericin B, 250 μg/mL) and 60 mM basolateral-to-apical Cl– gradient showing responses to 10 μM forskolin and 10 μM CFTRinh-172 without and with 20-minute pretreatment with 30 μM cinacalcet. (D) Summary of experiments as in C showing Δ ISC following forskolin and CFTRinh-172. (E) ISC traces with apical permeabilization (amphotericin B, 20 μΜ) and apical-to-basolateral K+ gradient showing responses to 10 μM forskolin and 5 mM barium chloride (BaCl2, cAMP-activated K+ channel inhibitor, added to basolateral side) without and with 20-minute pretreatment with 30 μM cinacalcet. (F) Summary of experiments as in E showing Δ ISC following forskolin and BaCl2. n = 5–6 experiments per group. Mean ± SEM, 1-way ANOVA with Newman-Keuls multiple comparisons test (B), and Student’s t test (D and F), *P < 0.05, ***P < 0.001.
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