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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2034-2040.
Prepublished online as a Blood First Edition Paper on May 10, 2007; DOI 10.1182/blood-2007-02-073700.
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Submitted February 9, 2007
Accepted April 28, 2007
AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo
Jing Yang, Takayuki Ikezoe*, Chie Nishioka, Taizo Tasaka, Ayuko Taniguchi, Yoshio Kuwayama, Naoki Komatsu, Kentaro Bandobashi, Kazuto Togitani, H.Phillip Koeffler, Hirokuni Taguchi, and Akihito Yokoyama
Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Japan
Division of Hematology, Department of Medicine, Kawasaki Medical School, Kurashiki, Japan
Department of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, United States
* Corresponding author; email: ikezoet{at}kochi-u.ac.jp.
Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. We have recently shown that hematopoietic malignant cells including those from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) aberrantly expressed Aurora A and B kinases, and ZM447439, a potent inhibitor of Aurora kinases, effectively induced growth arrest and apoptosis of a variety of leukemia cells. The present study explored the effect of AZD1152, a highly selective inhibitor of Aurora B kinase, on various types of human leukemia cells. AZD1152 inhibited the proliferation of AML lines (HL-60, NB4, MOLM13), ALL line (PALL-2), biphenotypic leukemia (MV4-11), acute eosinophilic leukemia (EOL-1), and the blast crisis of chronic myeloid leukemia K562 cells with an IC50 ranging from 3 to 40 nM, as measured by thymidine uptake on day 2 of culture. These cells had 4N/8N DNA content followed by apoptosis, as measured by cell cycle analysis and annexin V staining, respectively. Of note, AZD1152 synergistically enhanced the anti-proliferative activity of vincristine, a tubulin depolymerazing agent, or daunorubicin, a topoisomerase II inhibitor, against the MOLM13 and PALL-2 cells in vitro. Furthermore, AZD1152 potentiated the action of vincristine or daunorubicin in a MOLM13 murine xenograph model. Taken together, AZD1152 is a promising new agent for treatment of individuals with leukemia. The combined administration of AZD1152 and conventional chemotherapeutic agent to patients with leukemia warrants further investigation.
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