Selective Toxicity of Investigational Ixazomib for Human Leukemia Cells Expressing Mutant Cytoplasmic NPM1: Role of Reactive Oxygen Species

摘要: Purpose: This study was performed to determine whether the investigational proteasome inhibitor ixazomib demonstrated selective antineoplastic activity against acute myelogenous leukemia cells expressing a mutated nucleophosmin-1 gene and gain better understanding of its mechanisms action. Experimental Design: The cytotoxic effects treatment were analyzed in human (AML) cell lines primary AML samples wild-type or NPM1 (NPMc + ). potential roles oxidative stress mediating determined using flow cytometry, enzyme-based assays, Western blots. Results: Apoptosis induced by abrogated knockdown NPM1/NPMc expression an inducible shRNA construct enhanced NPMc overexpression. Cytotoxicity associated with superoxide generation reduced addition antioxidant N-acetylcysteine. had significantly levels intracellular glutathione NADPH responses drug treatment. Treatment 3 patients relapsed resulted antileukemic effect 1 patient as marked reduction leukemic blasts peripheral blood. Efficacy generation, levels, mRNA protein effectors responding cells. Conclusions: In this study, direct association observed between AML, responses, sensitivity oral that induces stress. These data suggest determinants may be good predictors therapeutic response ixazomib. Clin Cancer Res; 22(8); 1978–88. ©2015 AACR .