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J Cyst Fibros. 2016 Sep;15(5):568-78. doi: 10.1016/j.jcf.2016.04.007. Epub 2016 May 5.

Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations.

Author information

1
Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands; Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
2
Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
3
Department of Pediatric Pulmonology, Erasmus University Medical Centre/Sophia Children's Hospital, Rotterdam, the Netherlands.
4
Department of Pulmonology, University Medical Centre, Utrecht, The Netherlands.
5
Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Abstract

The potentiator VX-770 (ivacaftor/KALYDECOâ„¢) targets defective gating of CFTR and has been approved for treatment of cystic fibrosis (CF) subjects carrying G551D, S1251N or one of 8 other mutations. Still, the current potentiator treatment does not normalize CFTR-dependent biomarkers, indicating the need for development of more effective potentiator strategies. We have recently pioneered a functional CFTR assay in primary rectal organoids and used this model to characterize interactions between VX-770, genistein and curcumin, the latter 2 being natural food components with established CFTR potentiation capacities. Results indicated that all possible combinations of VX-770, genistein and curcumin synergistically repaired CFTR-dependent forskolin-induced swelling of organoids with CFTR-S1251N or CFTR-G551D, even under suboptimal CFTR activation and compounds concentrations, conditions that may predominate in vivo. Genistein and curcumin also enhanced forskolin-induced swelling of F508del homozygous organoids that were treated with VX-770 and the prototypical CFTR corrector VX-809. These results indicate that VX-770, genistein and curcumin in double or triple combinations can synergize in restoring CFTR-dependent fluid secretion in primary CF cells and support the use of multiple potentiators for treatment of CF.

KEYWORDS:

Curcumin; Cystic fibrosis; Genistein; Intestinal current measurements (ICM); Intestinal organoids; VX-770

PMID:
27160424
DOI:
10.1016/j.jcf.2016.04.007
[Indexed for MEDLINE]
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