Article ; Online: Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking.
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
2015 Volume 14, Issue 1, Page(s) 16–25
Abstract: Background: Small molecules as shown by VX809 can rescue the mislocalization of F508del-CFTR. The aim of this study was to identify correctors with a clinical history and their targets of action.: Methods: CFTR correctors were screened using two ... ...
| Abstract | Background: Small molecules as shown by VX809 can rescue the mislocalization of F508del-CFTR. The aim of this study was to identify correctors with a clinical history and their targets of action. Methods: CFTR correctors were screened using two F508del-CFTR expressing cell based HTS assays. Electrophysiological studies using CFBE41o(-) and HBE cells and in-vivo mouse assays confirmed CFTR rescue. The target of action was attained using pharmacological inhibitors and siRNA to specific genes. Results: Ibuprofen was identified as a CFTR corrector. Ibuprofen treatment of polarized CFBE41o(-) monolayers increased the short-circuit current (Isc) response to stimulation. In vivo CF mice treatment with ibuprofen restored the CFTR trafficking. SiRNA knock down of cyclooxygenase expression caused partial F508del-CFTR correction. Conclusion: These studies show that ibuprofen is a CFTR corrector and that it causes correction by COX-1 inhibition. Hence ibuprofen may be suitable to be part of a future CF combination therapy. |
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| MeSH term(s) | Animals ; Cell Movement/drug effects ; Cell Movement/genetics ; Cells, Cultured/drug effects ; Cyclooxygenase Inhibitors/pharmacology ; Cystic Fibrosis/drug therapy ; Cystic Fibrosis/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/drug effects ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Disease Models, Animal ; Humans ; Ibuprofen/pharmacology ; Mice ; Mice, Inbred CFTR ; Mutation ; Protein Transport/drug effects ; Protein Transport/genetics ; RNA, Small Interfering/genetics ; Reproducibility of Results ; Sensitivity and Specificity |
| Chemical Substances | Cyclooxygenase Inhibitors ; RNA, Small Interfering ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Ibuprofen (WK2XYI10QM) |
| Language | English |
| Publishing date | 2015-01 |
| Publishing country | Netherlands |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2091075-7 |
| ISSN | 1873-5010 ; 1569-1993 |
| ISSN (online) | 1873-5010 |
| ISSN | 1569-1993 |
| DOI | 10.1016/j.jcf.2014.06.001 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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