Abstract
Cystic Fibrosis (CF) due to the ΔF508 mutation of cystic fibrosis transmembrane conductance regulator (CFTR) can be treated with a combination of cysteamine and Epigallocatechin gallate (EGCG). Since ECGC is not a clinically approved drug, we attempted to identify other compounds that might favourably interact with cysteamine to induce autophagy and thus rescuing the function of ΔF508 CFTR as a chloride channel in the plasma membrane. For this, we screened a compound library composed by chemically diverse autophagy inducers for their ability to enhance autophagic flux in the presence of cysteamine. We identified the antiarrhythmic Ca2+ channel blocker amiodarone, as an FDA-approved drug having the property to cooperate with cysteamine to stimulate autophagy in an additive manner. Amiodarone promoted the re-expression of ΔF508 CFTR protein in the plasma membrane of respiratory epithelial cells. Hence, amiodarone might be yet another compound for the etiological therapy of CF in patients bearing the ΔF508 CFTR mutation.
Highlights
Introduction CysticFibrosis (CF) is the most frequent monogenetic lethal disease in human with a worldwide incidence of approximately 1:35001
This protocol was inspired by observations that were made previously in epithelial cells showing that the effects of cysteamine on CFTR stability was maintained several hours after cells were washed[27,28,33,46]
We have found that to Epigallocatechin gallate (EGCG), amiodarone was able to engage a cooperative interaction with cysteamine to stimulate autophagy in cultured biosensor cell lines
Summary
Fibrosis (CF) is the most frequent monogenetic lethal disease in human with a worldwide incidence of approximately 1:35001 This autosomal recessive disease occurring results from loss-of-function mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), a 1480-amino acid protein that acts as a cyclic adenosine monophosphate-gated chloride channel at the plasma membrane of different cells, mostly epithelial cells and macrophages[2,3,4]. CF can be caused by ~2000 different CFTR mutations, there is one single, highly prevalent mutation that accounts for ~85% of CF cases, consisting in the deletion of phenylalanine in position F508 (ΔF508)[12,13,14] This mutation affects the stability and turnover of the CFTR protein, causing its depletion from the plasma membrane and the loss of its function[15,16,17,18,19]
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