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-hydroxyquinazolinepyrazol-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. (Cancer Sci 2013; 104: 926-933)

The aurora kinases in cell cycle and leukemia

“…In one preclinical study, AZD1152 synergistically enhanced the anti-proliferative effects of vincristine and daunorubicin in vitro and in vivo 54 . In a second study, treatment with AZD1152 and cytarabine together caused a greater than additive cytotoxicity in leukemic cells in vitro 150 .…”

Aurora Kinases as Druggable Targets in Pediatric Leukemia: Heterogeneity in Target Modulation Activities and Cytotoxicity by Diverse Novel Therapeutic Agents

“…Importantly, the rational selection of Aurora kinase inhibitors in combination with chemotherapeutic agents or radiation may lead to increased cellular sensitivity to these therapeutic modalities. A number of studies have suggested the ability of Aurora kinase inhibitors to show synergy or potentiation with chemotherapies such as cytarabine [36] , vorinostat [37] , doxorubicin [27] , vincristine [38] , docetaxel [39] and daunorubicin [40] . In addition, the differential sensitivity of distinct leukemia subtypes such as high risk AML or BCR-ABL positive leukemia to Aurora kinase inhibitors should be explored further to optimize the efficacy of this family of agents [41] – [43] .…”

Venetoclax and alvocidib are both cytotoxic to acute myeloid leukemia cells resistant to cytarabine and clofarabine

“…The cytotoxicity of nucleoside analogs derives from inhibition of DNA synthesis, which is therefore S-phase specific [9,31]. Alvocidib reportedly inhibits CDK4 and CDK6, which regulate the cycling point, G1 -S [32][33][34][35].…”