title: Aurora B inhibitor barasertib and cytarabine exert a greater-than-additive cytotoxicity in acute myeloid leukemia cells.
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.
authors.affiliation: Department of Hematology and Oncology, University of Fukui, Fukui, Japan. tyamauch@u-fukui.ac.jp
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Kanako
authors.initials: K
authors.lastname: Uzui
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shigemi
authors.forename: Eiju
authors.initials: E
authors.lastname: Negoro
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshida
authors.forename: Takanori
authors.initials: T
authors.lastname: Ueda
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000008:administration & dosage; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D010755:Organophosphates / Q000008:administration & dosage; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage; D020298:U937 Cells
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D006657:Histones; D010755:Organophosphates; D011799:Quinazolines; D003561:Cytarabine; C576921:AURKB protein, human; D064107:Aurora Kinase B
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