apoptosis in Aurora-A-high acute myeloid leukemia Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces

Abstract Previously we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression of Aur-A was markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680-induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML ( P< .0001) or normal BMMCs ( P< .0001), suggesting the possible pharmacologic window in targeting Aurora kinase among Aur-A-high VX-680-sensitive leukemia patients. VX-680-induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G 2 /M phase arrest, decreased phosphorylated(p)-Akt-1 and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase (PARP). Notably, VX-680 increased Bax/Bcl-2 expression ratio, a favorable pro-apoptotic predictor for drug-response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and Aur-A-high expression may serve as a differential marker for selective treatment. From bloodjournal.hematologylibrary.org by guest on June 3, 2013. For personal use only.