Selective toxicity of investigational XXXX for @entity1 @entity1778 cells expressing mutant cytoplasmic @entity8102 : Role of reactive oxygen species.

@entity1 @entity137 @entity2041 @entity898 @entity3052 @entity1110 @entity1778 @entity34680 @entity8102 @entity224
PURPOSE: This study was performed to determine whether the investigational proteasome inhibitor @entity34680 demonstrated selective anti-neoplastic activity against @entity3052 cells expressing a mutated nucleophosmin-1 gene and to gain a better understanding of its mechanisms of action. EXPERIMENTAL DESIGN: The cytotoxic effects of @entity34680 treatment were analyzed in @entity1 @entity3052 cell lines and primary @entity3052 samples expressing wild type or mutated @entity8102 (NPMc+). The potential roles of oxidative stress in mediating cytotoxic activity were determined using flow cytometry, enzyme-based assays, and western blots. RESULTS: Apoptosis induced by @entity34680 was abrogated by knock down of @entity8102 /NPMc+ expression using an inducible shRNA construct and enhanced by NPMc+ overexpression. @entity137 was associated with @entity224 generation and was reduced by the addition of the antioxidant @entity898 . @entity3052 cells expressing NPMc+ had significantly reduced levels of intracellular @entity2041 and @entity1110 associated with reduced antioxidant responses to drug treatment. Treatment of three @entity1 with relapsed @entity3052 resulted in an anti- @entity1778 effect in one @entity1 as demonstrated by a marked @entity1778 in the peripheral blood. Efficacy was associated with @entity224 generation, reduced @entity2041 levels, and reduced mRNA and protein expression of antioxidant effectors in responding cells. CONCLUSION: In this study a direct association was observed between NPMc+ expression in @entity3052 , reduced antioxidant responses, and enhanced sensitivity to an oral proteasome inhibitor that induces oxidative stress. These data suggest that intracellular determinants of antioxidant responses may be good predictors of therapeutic response to @entity34680 .
