T. Yamauchi, Kanako Uzui, H. Shigemi
Jul 1, 2013
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0
Influential Citations
25
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Quality indicators
Journal
Cancer Science
Abstract
Barasertib, an aurora B inhibitor, terminates cell division, introduces polyploidy, and consequently causes apoptosis. In the present study, we evaluated the effect of the combination of barasertib and cytarabine (ara‐C), a key agent for leukemia chemotherapy, on leukemic cells in vitro. Human leukemia HL‐60 cells and HL‐60/ara‐C20 cells, a 20‐fold ara‐C‐resistant variant, were used. The 50% growth inhibitory concentrations of an active metabolite of barasertib, barasertib‐hydroxyquinazoline‐pyrazol‐aniline (Barasertib‐HQPA), and ara‐C were 51 nM and 300 nM for HL‐60 cells and 70 nM and 5300 nM for HL‐60/ara‐C20 cells, respectively. Barasertib‐HQPA induced polyploidy with a subsequent induction of sub‐G1 phase apoptosis, indicating the M‐phase specific cytotoxicity. Cells treated with the S‐phase specific ara‐C accumulated in S phase and subsequently died through apoptosis. When HL‐60 cells were treated with barasertib‐HQPA and ara‐C in combination, a greater‐than‐additive apoptosis was induced. This enhancement was obtained when the cells were treated with barasertib‐HQPA prior to ara‐C (37.9% sub‐G1) or with both concurrently (31.2% sub‐G1), but not with ara‐C prior to barasertib‐HQPA (17.8% sub‐G1). The combination effects were similarly obtained in HL‐60/ara‐C20 cells with 19.7% sub‐G1 for barasertib‐HQPA→ara‐C, 18.4% sub‐G1 for both concurrently, and 13.8% sub‐G1 for ara‐C→barasertib‐HQPA, and another leukemic U937 cells with 25.4% sub‐G1 for barasertib‐HQPA→ara‐C, 28.2% sub‐G1 for both concurrently, and 16.0% sub‐G1 for ara‐C→barasertib‐HQPA. Barasertib‐HQPA inhibited aurora B autophosphorylation and histone H3 phosphorylation in all the cell lines. Barasertib‐HQPA did not inhibit DNA synthesis, allowing ara‐C incorporation into DNA for its cytotoxicity. Thus, barasertib‐HQPA and ara‐C provided a greater‐than‐additive cytotoxicity in leukemic cells in vitro.