|
|
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.
 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:
|
|
|
|
 
J. Dutta-Simmons, Y. Zhang, G. Gorgun, M. Gatt, M. Mani, T. Hideshima, K. Takada, N. E. Carlson, D. E. Carrasco, Y.-T. Tai, et al.
Aurora kinase A is a target of Wnt/{beta}-catenin involved in multiple myeloma disease progression
Blood,
September 24, 2009;
114(13):
2699 - 2708.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Kaestner, A. Stolz, and H. Bastians
Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells
Mol. Cancer Ther.,
July 1, 2009;
8(7):
2046 - 2056.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
O. Decaux, L. Lode, F. Magrangeas, C. Charbonnel, W. Gouraud, P. Jezequel, M. Attal, J.-L. Harousseau, P. Moreau, R. Bataille, et al.
Prediction of Survival in Multiple Myeloma Based on Gene Expression Profiles Reveals Cell Cycle and Chromosomal Instability Signatures in High-Risk Patients and Hyperdiploid Signatures in Low-Risk Patients: A Study of the Intergroupe Francophone du Myelome
J. Clin. Oncol.,
October 10, 2008;
26(29):
4798 - 4805.
[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]
|
|
|
|
|
