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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 6

Cinacalcet prevents cholera toxin–induced and STa toxin–induced fluid accumulation in intestinal closed loops in mice.

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Cinacalcet prevents cholera toxin–induced and STa toxin–induced fluid ac...
(A) Experimental protocol for measurement of fluid accumulation in midjejunal closed loops in mice. (B) Weight/length ratio and representative photos of loops injected with phosphate-buffered saline (PBS) or 1 μg cholera toxin (± 10 μM tenapanor) in WT mice pretreated with cinacalcet (1, 10, or 30 mg/kg, ip) or vehicle. n = 6–16 loops per group. (C) Weight/length ratio and representative photos of loops injected with PBS or 0.1 μg STa toxin in WT mice pretreated with cinacalcet (1, 10, or 30 mg/kg, ip) or vehicle. n = 4–6 loops per group. (D) Weight/length ratio of loops injected with PBS or 1 μg cholera toxin (± 10 μM tenapanor) in cystic fibrosis (CF, ΔF508 homozygous) mice pretreated with cinacalcet (30 mg/kg, ip) or vehicle. n = 5 loops per group. Mean ± SEM, 1-way ANOVA with Newman-Keuls multiple comparisons test, *P < 0.05, **P < 0.01, ***P < 0.001.
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