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Research Articles: Therapeutics, Targets, and Development

A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia

¹ Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, Japan; ² Division of Hematology, Department of Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan; and ³ Department of Hematology and Oncology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, California

Requests for reprints: Takayuki Ikezoe, Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi 783-8505, Japan. Phone: 81-88-880-2345; Fax: 81-88-880-2348. E-mail: ikezoet{at}kochi-u.ac.jp

Abstract

The Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Aberrant expression of these kinases occurs in solid tumors and is associated with aneuploidy and carcinogenesis. We found in this study that Aurora kinase A and B were aberrantly expressed in a variety of types of human leukemia cell lines (n = 15, e.g., PALL-1, PALL-2, HL-60, NB4, MV4-11, etc.), as well as freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n = 44) compared with bone marrow mononuclear cells from healthy volunteers (n = 11), as measured by real-time PCR. ZM447439 is a novel selective Aurora kinase inhibitor. The compound induced growth inhibition, caused accumulation of cells with 4N/8N DNA content, and mediated apoptosis of human leukemia cells as measured by thymidine uptake, cell cycle analysis, and annexin V staining, respectively. Especially profound growth inhibition occurred with the PALL-1 and PALL-2 cells, which possess wild-type p53 gene. In contrast, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy normal volunteers. Taken together, inhibition of Aurora kinases may be a promising treatment strategy for individuals with leukemia. [Mol Cancer Ther 2007;6(6):1851–7]

Grant support: Grant-in-Aid from the Ministry of Education, Culture Sports, Science, and Technology of Japan, Uehara Memorial Foundation, Public Trust of Hraguchi Cancer Research Memorial Foundation, AstraZeneca Research Grant. H.P. Koeffler is supported by NIH grants, as well as the Inger Fund and the Parker Hughes Trust.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/30/07; revised 4/16/07; accepted 4/27/07.

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