Faculty of Medicine, University of Paris Sud-Saclay, Kremlin-Bicêtre, France.
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
Cell Death Dis. 2018 Feb 7;9(2):191. doi: 10.1038/s41419-017-0235-9.
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 Ca 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.
囊性纤维化（CF）是由囊性纤维化跨膜电导调节因子（CFTR）的ΔF508 突变引起的，可以用半胱胺和表没食子儿茶素没食子酸酯（EGCG）的组合来治疗。由于 EGCG 不是一种临床批准的药物，我们试图寻找其他可能与半胱胺有利相互作用的化合物，以诱导自噬，从而恢复ΔF508 CFTR 作为质膜中氯离子通道的功能。为此，我们筛选了一个由化学上不同的自噬诱导剂组成的化合物库，以确定它们在半胱胺存在的情况下增强自噬流的能力。我们发现抗心律失常钙通道阻滞剂胺碘酮是一种 FDA 批准的药物，具有与半胱胺协同作用以附加方式刺激自噬的特性。胺碘酮促进了呼吸上皮细胞质膜中ΔF508 CFTR 蛋白的重新表达。因此，胺碘酮可能是另一种用于携带ΔF508 CFTR 突变的患者的 CF 病因治疗的化合物。
