Inhibition of Mitochondrial Translation as a Therapeutic Strategy for Human Acute Myeloid Leukemia
Menée sur des lignées cellulaires de leucémie, cette étude suggère que l'inhibition du mécanisme de traduction dans les mitochondries représente une stratégie intéressante pour le traitement des leucémies myéloïdes aiguës
To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed antileukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the antileukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis that, together with an increased basal oxygen consumption, proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tigecycline sensitivity. º Inhibition of mitochondrial translation has antileukemia activity º AML cells have higher mitochondrial biogenesis than normal hematopoietic cells º Mitochondrial translation inhibition is a therapeutic strategy for AML º Tigecycline is a potential therapeutic agent for AML therapy
Cancer cell , résumé, 2010