Glioblastoma multiforme (GBM) is one of the most common and aggressive types of primary brain tumor. After complete surgical resection combined with radiation and chemotherapy, approximately 10% of patients survive for more than 5 years. Therefore, a novel therapy for GBM is needed. Aurora-A (AURKA) plays important roles in cell cycle regulation, such as centrosome maturation, chromatic separation, bipolar spindle assembly, and mitotic entry. To investigate the effects of AURKA inhibition, three GBM cell lines, including GBM 8401, GBM 8901, and U87-MG cells, were treated with the AURKA inhibitor VE-465. Sensitivities to VE-465, as indicated by 50% inhibitory concentration values for GBM 8401, GBM 8901, and U87-MG cells, were 6, 25, and 19 nM, respectively. Additionally, colony formation of GBM 8401 and GBM 8901 cells was decreased after treatment with the VE-465. VE-465 treatment increased polyploidy and p53 protein expression, and inhibited cell growth in a caspase-independent manner. Taken together, these results suggest that the inhibition of AURKA by a small-molecule inhibitor may have potential to serve as a novel therapeutic approach for GBM.

Sathornsumetee S, Rich JN: Designer therapies for glioblastoma multiforme. Ann NY Acad Sci 2008;1142:108-132.
Stupp R, Hegi ME, Gilbert MR, Chakravarti A: Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol 2007;25:4127-4136.
Mason WP, Cairncross JG: Drug insight: temozolomide as a treatment for malignant glioma - impact of a recent trial. Nat Clin Pract Neurol 2005;1:88-95.
Reardon DA, Rich JN, Friedman HS, Bigner DD: Recent advances in the treatment of malignant astrocytoma. J Clin Oncol 2006;24:1253-1265.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-466.
Huang PH, Cavenee WK, Furnari FB, White FM: Uncovering therapeutic targets for glioblastoma: a systems biology approach. Cell Cycle 2007;6:2750-2754.
Reardon DA, Wen PY: Therapeutic advances in the treatment of glioblastoma: rationale and potential role of targeted agents. Oncologist 2006;11:152-164.
Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A, Brinkley BR, Sen S: Tumour amplified kinase stk15/btak induces centrosome amplification, aneuploidy and transformation. Nat Genet 1998;20:189-193.
Takahashi T, Futamura M, Yoshimi N, Sano J, Katada M, Takagi Y, Kimura M, Yoshioka T, Okano Y, Saji S: Centrosomal kinases, HsAIRK1 and HsAIRK3, are overexpressed in primary colorectal cancers. Jpn J Cancer Res 2000;91:1007-1014.
Gritsko TM, Coppola D, Paciga JE, Yang L, Sun M, Shelley SA, Fiorica JV, Nicosia SV, Cheng JQ: Activation and overexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Clin Cancer Res 2003;9:1420-1426.
Li D, Zhu J, Firozi PF, Abbruzzese JL, Evans DB, Cleary K, Friess H, Sen S: Overexpression of oncogenic STK15/Btak/Aurora A kinase in human pancreatic cancer. Clin Cancer Res 2003;9:991-997.
Neben K, Korshunov A, Benner A, Wrobel G, Hahn M, Kokocinski F, Golanov A, Joos S, Lichter P: Microarray-based screening for molecular markers in medulloblastoma revealed STK15 as independent predictor for survival. Cancer Res 2004;64:3103-3111.
Lehman NL, O'Donnell JP, Whiteley LJ, Stapp RT, Lehman TD, Roszka KM, Schultz LR, Williams CJ, Mikkelsen T, Brown SL, Ecsedy JA, Poisson LM: Aurora A is differentially expressed in gliomas, is associated with patient survival in glioblastoma and is a potential chemotherapeutic target in gliomas. Cell Cycle 2012;11:489-502.
Evans R, Naber C, Steffler T, Checkland T, Keats J, Maxwell C, Perry T, Chau H, Belch A, Pilarski L, Reiman T: Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells. Leuk Lymphoma 2008;49:559-569.
Lin ZZ, Hsu HC, Hsu CH, Yeh PY, Huang CY, Huang YF, Chen TJ, Kuo SH, Hsu C, Hu FC, Jeng YM, Chung Y, Cheng AL: The Aurora kinase inhibitor VE-465 has anticancer effects in pre-clinical studies of human hepatocellular carcinoma. J Hepatol 2009;50:518-527.
Araki K, Nozaki K, Ueba T, Tatsuka M, Hashimoto N: High expression of Aurora-B/Aurora and IpLL-like midbody-associated protein (AIM-1) in astrocytomas. J Neurooncol 2004;67:53-64.
Tsuno T, Natsume A, Katsumata S, Mizuno M, Fujita M, Osawa H, Nakahara N, Wakabayashi T, Satoh Y, Inagaki M, Yoshida J: Inhibition of Aurora-B function increases formation of multinucleated cells in p53 gene deficient cells and enhances anti-tumor effect of temozolomide in human glioma cells. J Neurooncol 2007;83:249-258.
Zeng WF, Navaratne K, Prayson RA, Weil RJ: Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme. J Clin Pathol 2007;60:218-221.
Soderberg O, Gullberg M, Jarvius M, Ridderstrale K, Leuchowius KJ, Jarvius J, Wester K, Hydbring P, Bahram F, Larsson LG, Landegren U: Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nature Methods 2006;3:995-1000.
Huang YH, Wu CC, Chou CK, Huang CY: A translational regulator, PUM2, promotes both protein stability and kinase activity of Aurora-A. PloS One 2011;6:e19718.
Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C: Clonogenic assay of cells in vitro. Nat Protoc 2006;1:2315-2319.
Mrugala MM, Chamberlain MC: Mechanisms of disease: temozolomide and glioblastoma - look to the future. Nat Clin Pract Oncol 2008;5:476-486.
Hart MG, Grant R, Garside R, Rogers G, Somerville M, Stein K: Temozolomide for high grade glioma. Cochrane Database Syst Rev 2008;4:CD007415.
Macdonald DR: Temozolomide for recurrent high-grade glioma. Semin Oncol 2001;28:3-12.
Oshiro S, Tsugu H, Komatsu F, Ohmura T, Ohta M, Sakamoto S, Fukushima T, Inoue T: Efficacy of temozolomide treatment in patients with high-grade glioma. Anticancer Res 2009;29:911-917.
Ruggiero A, Cefalo G, Garre ML, Massimino M, Colosimo C, Attina G, Lazzareschi I, Maurizi P, Ridola V, Mazzarella G, Caldarelli M, Di Rocco C, Madon E, Abate ME, Clerico A, Sandri A, Riccardi R: Phase II trial of temozolomide in children with recurrent high-grade glioma. J Neurooncol 2006;77:89-94.
Schonekaes K, Mucke R, Panke J, Rama B, Wagner W: Combined radiotherapy and temozolomide in patients with recurrent high grade glioma. Tumori 2002;88:28-31.
Tafuto S, Muto P, Tortoriello A, Pisano A, Comella P, Formato R, Quattrin S, Iaffaioli RV: Phase I study of temozolomide and lomustine in the treatment of high grade malignant glioma. Front Biosci 2006;11:502-505.
Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P, Meuli R, Janzer R, Pizzolato G, Miralbell R, Porchet F, Regli L, de Tribolet N, Mirimanoff RO, Leyvraz S: Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 2002;20:1375-1382.
Hsu JY, Sun ZW, Li X, Reuben M, Tatchell K, Bishop DK, Grushcow JM, Brame CJ, Caldwell JA, Hunt DF, Lin R, Smith MM, Allis CD: Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes. Cell 2000;102:279-291.
Ducat D, Zheng Y: Aurora kinases in spindle assembly and chromosome segregation. Exp Cell Res 2004;301:60-67.
Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T, Graham JA, Demur C, Hercend T, Diu-Hercend A, Su M, Golec JM, Miller KM: Vx-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 2004;10:262-267.
Ditchfield C, Johnson VL, Tighe A, Ellston R, Haworth C, Johnson T, Mortlock A, Keen N, Taylor SS: Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol 2003;161:267-280.
Long ZJ, Xu J, Yan M, Zhang JG, Guan Z, Xu DZ, Wang XR, Yao J, Zheng FM, Chu GL, Cao JX, Zeng YX, Liu Q: Zm 447439 inhibition of aurora kinase induces Hep2 cancer cell apoptosis in three-dimensional culture. Cell Cycle 2008;7:1473-1479.
Sun L, Li D, Dong X, Yu H, Dong JT, Zhang C, Lu X, Zhou J: Small-molecule inhibition of aurora kinases triggers spindle checkpoint-independent apoptosis in cancer cells. Biochem Pharmacol 2008;75:1027-1034.
Yang J, Ikezoe T, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, Komatsu N, Bandobashi K, Togitani K, Koeffler HP, Taguchi H, Yokoyama A: AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood 2007;110:2034-2040.
Oke A, Pearce D, Wilkinson RW, Crafter C, Odedra R, Cavenagh J, Fitzgibbon J, Lister AT, Joel S, Bonnet D: AZD1152 rapidly and negatively affects the growth and survival of human acute myeloid leukemia cells in vitro and in vivo. Cancer Res 2009;69:4150-4158.
Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F, Fujii S, Arlinghaus RB, Czerniak BA, Sen S: Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet 2004;36:55-62.
Liu Q, Kaneko S, Yang L, Feldman RI, Nicosia SV, Chen J, Cheng JQ: Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215. J Biol Chem 2004;279:52175-52182.
Barton VN, Foreman NK, Donson AM, Birks DK, Handler MH, Vibhakar R: Aurora kinase A as a rational target for therapy in glioblastoma. J Neurosurg Pediatr 2010;6:98-105.
Diaz RJ, Golbourn B, Shekarforoush M, Smith CA, Rutka JT: Aurora kinase B/C inhibition impairs malignant glioma growth in vivo. J Neurooncol 2012;108:349-360.
Borges KS, Castro-Gamero AM, Moreno DA, da Silva Silveira V, Brassesco MS, de Paula Queiroz RG, de Oliveira HF, Carlotti CG Jr, Scrideli CA, Tone LG: Inhibition of aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells. J Cancer Res Clin Oncol 2012;138:405-414.
Wilkinson RW, Odedra R, Heaton SP, Wedge SR, Keen NJ, Crafter C, Foster JR, Brady MC, Bigley A, Brown E, Byth KF, Barrass NC, Mundt KE, Foote KM, Heron NM, Jung FH, Mortlock AA, Boyle FT, Green S: AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apopto sis. Clin Cancer Res 2007;13:3682-3688.
Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G: Cell death by mitotic catastrophe: a molecular definition. Oncogene 2004;23:2825-2837.
Mansilla S, Priebe W, Portugal J: Mitotic catastrophe results in cell death by caspase-dependent and caspase-independent mechanisms. Cell Cycle 2006;5:53-60.
Vakifahmetoglu H, Olsson M, Zhivotovsky B: Death through a tragedy: mitotic catastrophe. Cell Death Differ 2008;15:1153-1162.
Broker LE, Kruyt FA, Giaccone G: Cell death independent of caspases: a review. Clin Cancer Res 2005;11:3155-3162.
de Bruin EC, Medema JP: Apoptosis and non-apoptotic deaths in cancer development and treatment response. Cancer Treat Rev 2008;34:737-749.
Molz L, Booher R, Young P, Beach D: cdc2 and the regulation of mitosis: six interacting mcs genes. Genetics 1989;122:773-782.
Andreassen PR, Lacroix FB, Lohez OD, Margolis RL: Neither p21WAF1 nor 14-3-3sigma prevents G2 progression to mitotic catastrophe in human colon carcinoma cells after DNA damage, but p21WAF1 induces stable G1 arrest in resulting tetraploid cells. Cancer Res 2001;61:7660-7668.
Guardavaccaro D, Kudo Y, Boulaire J, Barchi M, Busino L, Donzelli M, Margottin-Goguet F, Jackson PK, Yamasaki L, Pagano M: Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo. Dev Cell 2003;4:799-812.
Toledo F, Wahl GM: Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 2006;6:909-923.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.