This Article Full Text Full Text (PDF) All Versions of this Article: 1535-7163.MCT-07-0067v1 6/6/1851    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ikezoe, T. Articles by Taguchi, H. Search for Related Content PubMed PubMed Citation Articles by Ikezoe, T. Articles by Taguchi, H.

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.

This article has been cited by other articles:

				K. Kojima, M. Konopleva, T. Tsao, H. Nakakuma, and M. Andreeff Concomitant inhibition of Mdm2-p53 interaction and Aurora kinases activates the p53-dependent postmitotic checkpoints and synergistically induces p53-mediated mitochondrial apoptosis along with reduced endoreduplication in acute myelogenous leukemia Blood, October 1, 2008; 112(7): 2886 - 2895. [Abstract] [Full Text] [PDF]

				L.-Y. Hung, J. T. Tseng, Y.-C. Lee, W. Xia, Y.-N. Wang, M.-L. Wu, Y.-H. Chuang, C.-H. Lai, and W.-C. Chang Nuclear epidermal growth factor receptor (EGFR) interacts with signal transducer and activator of transcription 5 (STAT5) in activating Aurora-A gene expression Nucleic Acids Res., August 1, 2008; 36(13): 4337 - 4351. [Abstract] [Full Text] [PDF]

				C. Nishioka, T. Ikezoe, J. Yang, A. Miwa, T. Tasaka, Y. Kuwayama, K. Togitani, H. P. Koeffler, and A. Yokoyama Ki11502, a novel multitargeted receptor tyrosine kinase inhibitor, induces growth arrest and apoptosis of human leukemia cells in vitro and in vivo Blood, May 15, 2008; 111(10): 5086 - 5092. [Abstract] [Full Text] [PDF]

				A. M. D'Alise, G. Amabile, M. Iovino, F. P. Di Giorgio, M. Bartiromo, F. Sessa, F. Villa, A. Musacchio, and R. Cortese Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells Mol. Cancer Ther., May 1, 2008; 7(5): 1140 - 1149. [Abstract] [Full Text] [PDF]

				X.-F. Huang, S.-K. Luo, J. Xu, J. Li, D.-R. Xu, L.-H. Wang, M. Yan, X.-R. Wang, X.-B. Wan, F.-M. Zheng, et al. Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia Blood, March 1, 2008; 111(5): 2854 - 2865. [Abstract] [Full Text] [PDF]