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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3915-3921. Prepublished online as a Blood First Edition Paper on January 9, 2007; DOI 10.1182/blood-2006-07-037671. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-07-037671v1 109/9/3915    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shi, Y. Articles by Lichtenstein, A. Search for Related Content PubMed PubMed Citation Articles by Shi, Y. Articles by Lichtenstein, A. Related Collections Neoplasia Cytoskeleton Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Targeting aurora kinases as therapy in multiple myeloma Yijiang Shi1, Tony Reiman3, Weiqun Li2, Christopher A. Maxwell3, Subrata Sen4, Linda Pilarski3, Tracy R. Daniels1, Manuel L. Penichet1, Rick Feldman5, and Alan Lichtenstein1 1 Division of Hematology, Veterans Administration (VA) West Los Angeles (LA)–University of California Los Angeles (UCLA) Medical School and Jonsson Cancer Center, Department of Surgery, UCLA Medical School; 2 Origene Technologies, Rockville, MD; 3 Department of Oncology, University of Alberta and Cross Cancer Institute, Alberta, Canada; 4 Department of Molecular Pathology, M. D. Anderson Cancer Center, Houston, TX, and Department of Cancer Research; 5 Berlex Biosciences, Richmond, CA The aurora kinases facilitate transit from G2 through cytokinesis and, thus, are targets in cancer therapy. Multiple myeloma (MM) is a malignancy characterized by genetic instability, suggesting a disruption of checkpoints that arrest cells at G2M when injury to the mitotic machinery occurs. Since deficient checkpoints would prevent cell cycle arrest and may render cells susceptible to apoptosis in mitosis and since aurora kinases are intermediaries in checkpoint pathways, we tested antimyeloma effects of 2 agents that inhibit aurora kinases. Both inhibited growth of MM lines and primary myeloma samples at nanomolar concentrations while having less of an effect on proliferating lymphocytes and hematopoietic cells. MM cells were not protected by IL-6 or activating mutations of Ras. Antimyeloma effects included induction of tetraploidy followed by apoptosis. Apoptosis correlated with inhibition of aurora activity as shown by reduction of histone 3B phosphorylation. Ectopic expression of aurora A protected MM cells against aurora inhibitors but had no effect on apoptosis induced by bortezomib. As expression of RHAMM in MM contributes to genetic instability, we tested effects of RHAMM. RHAMM overexpression enhanced sensitivity to apoptosis and RHAMM silencing decreased sensitivity. These results suggest potential for aurora kinase inhibitors in MM especially in patients in whom RHAMM is overexpressed. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Hideshima, D. Chauhan, T. Kiziltepe, H. Ikeda, Y. Okawa, K. Podar, N. Raje, A. Protopopov, N. C. Munshi, P. G. Richardson, et al. Biologic sequelae of I{kappa}B kinase (IKK) inhibition in multiple myeloma: therapeutic implications Blood, May 21, 2009; 113(21): 5228 - 5236. [Abstract] [Full Text] [PDF] D. Hose, T. Reme, T. Meissner, J. Moreaux, A. Seckinger, J. Lewis, V. Benes, A. Benner, M. Hundemer, T. Hielscher, et al. Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma Blood, April 30, 2009; 113(18): 4331 - 4340. [Abstract] [Full Text] [PDF] T. Ochi, H. Fujiwara, K. Suemori, T. Azuma, Y. Yakushijin, T. Hato, K. Kuzushima, and M. Yasukawa Aurora-A kinase: a novel target of cellular immunotherapy for leukemia Blood, January 1, 2009; 113(1): 66 - 74. [Abstract] [Full Text] [PDF] Y. Shi, P. J. Frost, B. Q. Hoang, A. Benavides, S. Sharma, J. F. Gera, and A. K. Lichtenstein IL-6-Induced Stimulation of c-Myc Translation in Multiple Myeloma Cells Is Mediated by Myc Internal Ribosome Entry Site Function and the RNA-Binding Protein, hnRNP A1 Cancer Res., December 15, 2008; 68(24): 10215 - 10222. [Abstract] [Full Text] [PDF] H. H. Lee, Y. Zhu, K. M Govindasamy, and G. Gopalan Downregulation of Aurora-A overrides estrogen-mediated growth and chemoresistance in breast cancer cells Endocr. Relat. Cancer, September 1, 2008; 15(3): 765 - 775. [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] W. J. Chng, E. Braggio, G. Mulligan, B. Bryant, E. Remstein, R. Valdez, A. Dogan, and R. Fonseca The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition Blood, February 1, 2008; 111(3): 1603 - 1609. [Abstract] [Full Text] [PDF] Z. Guan, X.-r. Wang, X.-f. Zhu, X.-f. Huang, J. Xu, L.-h. Wang, X.-b. Wan, Z.-j. Long, J.-n. Liu, G.-k. Feng, et al. Aurora-A, a Negative Prognostic Marker, Increases Migration and Decreases Radiosensitivity in Cancer Cells Cancer Res., November 1, 2007; 67(21): 10436 - 10444. [Abstract] [Full Text] [PDF]

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