Izzo Valentina, Pietrocola Federico, Sica Valentina, Durand Sylvère, Lachkar Sylvie, Enot David, Bravo-San Pedro José Manuel, Chery Alexis, Esposito Speranza, Raia Valeria, Maiuri Luigi, Maiuri Maria Chiara, Kroemer Guido
a Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers , INSERM U 1138, Paris , France.
b Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
Cell Cycle. 2017 Feb;16(3):271-279. doi: 10.1080/15384101.2016.1249550. Epub 2017 Jan 6.
Phase II clinical trials indicate that the combination of cysteamine plus epigallocatechin gallate (EGCG) is effective against cystic fibrosis in patients bearing the most frequent etiological mutation (CFTRΔF508). Here, we investigated the interaction between both agents on cultured respiratory epithelia cells from normal and CFTRΔF508-mutated donors. We observed that the combination of both agents affected metabolic circuits (and in particular the tricarboxylic acid cycle) in a unique way and that cysteamine plus EGCG reduced cytoplasmic protein acetylation more than each of the 2 components alone. In a cell-free system, protein cross-linking activity of EGCG was suppressed by cysteamine. Finally, EGCG was able to enhance the conversion of cysteamine into taurine in metabolic flux experiments. Altogether, these results indicate that multiple pharmacological interactions occur between cysteamine and EGCG, suggesting that they contribute to the unique synergy of both agents in restoring the function of mutated CFTRΔF508.
II期临床试验表明，半胱胺加表没食子儿茶素没食子酸酯（EGCG）的组合对携带最常见病因突变（CFTRΔF508）的囊性纤维化患者有效。在此，我们研究了这两种药物对来自正常和CFTRΔF508突变供体的培养呼吸道上皮细胞的相互作用。我们观察到，这两种药物的组合以独特的方式影响代谢途径（特别是三羧酸循环），并且半胱胺加EGCG比单独的两种成分中的任何一种更能降低细胞质蛋白乙酰化。在无细胞系统中，半胱胺抑制了EGCG的蛋白质交联活性。最后，在代谢通量实验中，EGCG能够增强半胱胺向牛磺酸的转化。总之，这些结果表明半胱胺和EGCG之间发生了多种药理相互作用，表明它们有助于两种药物在恢复突变的CFTRΔF508功能方面的独特协同作用。
