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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2854-2865. Prepublished online as a Blood First Edition Paper on December 26, 2007; DOI 10.1182/blood-2007-07-099325. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2007-07-099325v1 111/5/2854    most recent Alert me when this article is cited Alert me if a correction is posted 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 Huang, X.-F. Articles by Liu, Q. Search for Related Content PubMed PubMed Citation Articles by Huang, X.-F. Articles by Liu, Q. Social Bookmarking                   What's this?  Previous Article Submitted July 6, 2007 Accepted December 16, 2007 Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia Xue-Fei Huang, Shao-Kai Luo, Jie Xu, Juan Li, Duo-Rong Xu, Li-Hui Wang, Min Yan, Xian-Ren Wang, Xiang-Bo Wan, Fei-Meng Zheng, Yi-Xin Zeng, and Quentin Liu* State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China Department of Hematology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China * Corresponding author; email: liuq9{at}mail.sysu.edu.cn. Previously we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression of Aur-A was markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680-induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P<.0001) or normal BMMCs (P<.0001), suggesting the possible pharmacologic window in targeting Aurora kinase among Aur-A-high VX-680-sensitive leukemia patients. VX-680-induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G2/M phase arrest, decreased phosphorylated(p)-AKT-1 and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase (PARP). Notably, VX-680 increased Bax/Bcl-2 expression ratio, a favorable pro-apoptotic predictor for drug-response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and Aur-A-high expression may serve as a differential marker for selective treatment. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. S. Boss, J. H. Beijnen, and J. H.M. Schellens Clinical Experience with Aurora Kinase Inhibitors: A Review Oncologist, August 1, 2009; 14(8): 780 - 793. [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] X.-B. Wan, Z.-J. Long, M. Yan, J. Xu, L.-P. Xia, L. Liu, Y. Zhao, X.-F. Huang, X.-R. Wang, X.-F. Zhu, et al. Inhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells Carcinogenesis, October 1, 2008; 29(10): 1930 - 1937. [Abstract] [Full Text] [PDF]

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