The majority of patients with acute myeloid leukemia (AML) initially achieve complete remission by cytarabine (ara-C)-based chemotherapy, but many relapse with resistant disease. Aurora B kinase is involved in the spindle assembly checkpoint component of the mitotic process. Barasertib (formerly AZD1152), a selective inhibitor of aurora B kinase, provided an overall hematological response rate of 25% in AML patients in a phase I/II study, which warrants further investigation. To see the feasibility of the incorporation of this new agent to the standard induction chemotherapy, we evaluated the combination effect of barasertib with ara-C against leukemic cells in vitro. Cultured human leukemia HL-60 cells and ara-C-resistant variant HL-60/ara-C cells were used. Growth inhibition effects were evaluated by using the XTT assay. The cell cycle distribution and the induction of apoptosis were determined by flowcytometric analysis. Autophosphorylation of aurora B was assessed by Western blotting. The XTT assay determined that the 50%-growth inhibitory concentrations of ara-C were 100 - 300 nM for HL-60 cells and 4,000 - 5,000 nM for HL-60/ara-C cells, respectively. When HL-60 cells were treated with barasertib-hQPA, the active compound of barasertib, the cells exhibited an increase in the percentage of > 4N at 48 h with the subsequent induction of sub-G1 population. Autophosphorylation of aurora B was inhibited by barasertib-hQPA simultaneously. When the cells were treated with ara-C, the accumulation at G2-M phase and the subsequent increase in sub-G1 phase were observed. When the cells were treated with barasertib-hQPA and ara-C in combination, the treatment induced the greater-than-additive induction of sub-G1 population. However, the augmentation was brought about only when the cells were treated with barasertib prior to ara-C or both simultaneously. Barasertib-hQPA similarly altered the cell cycle, inhibited autophosphorylation of auroa B, and induced apoptosis in HL-60/ara-C cells. Low concentrations of ara-C failed to modify cell cycle distribution without the induction of apoptosis in HL-60/ara-C cells. Nevertheless, the sequential combination between barasertib-hQPA and a moderate concentration of ara-C augmented the sub-G1 population. In conclusion, the combination of barasertib with ara-C provided greater cytotoxicity than barasertib alone in both ara-C-sensitive and ara-C-resistant AML cell lines in vitro. The sequential administration of barasertib with ara-C may be promising against ara-C-refractory AML.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2818. doi:1538-7445.AM2012-2818