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The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation

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Abstract

The selective Aurora-A kinase inhibitor MLN8237 is in clinical trials for hematologic malignancies, ovarian cancer and other solid tumors. We previously showed that MLN8237 is potently antiproliferative toward standard monolayer-cultured glioblastoma cells. We have now investigated the effect of MLN8237 with and without temozolomide or ionizing radiation on the proliferation of glioblastoma tumor stem-like cells (neurospheres) using soft agar colony formation assays and normal human astrocytes by MTT assay. Western blotting was utilized to compare MLN8237 IC50s to cellular Aurora-A and phosphoThr288Aurora-A levels. MLN8237 was more potently antiproliferative to neurosphere cells than to standard monolayer glioma cells, and was non-toxic to normal human astrocytes. Western blot analysis revealed that MLN8237 treatment inhibits phosphoThr288Aurora-A levels providing proof of drug target-hit in glioblastoma cells. Furthermore, phosphoThr288Aurora-A levels partially predicted the antiproliferative efficacy of MLN8237. We also found that Aurora-A inhibition by MLN8237 was synergistic with temozolomide and potentiated the effects of ionizing radiation on colony formation in neurosphere glioblastoma tumor stem-like cells. These results further support the potential of Aurora-A inhibitors as primary chemotherapy agents or biologic response modifiers in glioblastoma patients.

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References

  1. ClinicalTrials.gov, a service of the U.S. National Institutes of Health. www.clinicaltrials.gov. Accessed 12 Oct 2013

  2. Kelly KR, Ecsedy J, Medina E, Mahalingam D, Padmanabhan S, Nawrocki ST, Giles FJ, Carew JS (2011) The novel Aurora A kinase inhibitor MLN8237 is active in resistant chronic myeloid leukemia and significantly increases the efficacy of nilotinib. J Cell Mol Med 15:2057–2070

    Article  CAS  PubMed  Google Scholar 

  3. Görgün G, Calabrese E, Hideshima T, Ecsedy J, Perrone G, Mani M, Ikeda H, Bianchi G, Hu Y, Cirstea D, Santo L, Tai YT, Nahar S, Zheng M, Bandi M, Carrasco RD, Raje N, Munshi N, Richardson P, Anderson KC (2010) A novel aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell cycle arrest in multiple myeloma. Blood 115:5202–5213

    Article  PubMed Central  PubMed  Google Scholar 

  4. Manfredi MG, Ecsedy JA, Chakravarty A, Silverman L, Zhang M, Hoar KM, Stroud SG, Chen W, Shinde V, Huck JJ, Wysong DR, Janowick DA, Hyer ML, Leroy PJ, Gershman RE, Silva MD, Germanos MS, Bolen JB, Claiborne CF, Sells TB (2011) Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res 17:7614–7624

    Article  CAS  PubMed  Google Scholar 

  5. Dees EC, Cohen RB, von Mehren M, Stinchcombe TE, Liu H, Venkatakrishnan K, Manfredi M, Fingert H, Burris HA 3rd, Infante JR (2012) Phase I study of aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res 18:4775–4784

    Article  CAS  PubMed  Google Scholar 

  6. Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A, Brinkley BR, Sen S (1998) Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 20:189–193

    Article  CAS  PubMed  Google Scholar 

  7. Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E, Saya H (2003) Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem 278:51786–51795

    Article  CAS  PubMed  Google Scholar 

  8. Seki A, Coppinger JA, Jang CY, Yates JR, Fang G (2008) Bora and the kinase Aurora A cooperatively activate the kinase Plk1 and control mitotic entry. Science 320:1655–1658

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Carol H, Boehm I, Reynolds CP, Kang MH, Maris JM, Morton CL, Gorlick R, Kolb EA, Keir ST, Wu J, Wozniak AE, Yang Y, Manfredi M, Ecsedy J, Wang J, Neale G, Houghton PJ, Smith MA, Lock RB (2011) Efficacy and pharmacokinetic/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer. Cancer Chemother Pharmacol 68:1291–1304

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Huck JJ, Zhang M, McDonald A, Bowman D, Hoar KM, Stringer B, Ecsedy J, Manfredi MG, Hyer ML (2010) MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo. Mol Cancer Res 8:373–384

    Article  CAS  PubMed  Google Scholar 

  11. Otto T, Horn S, Brockmann M, Eilers U, Schüttrumpf L, Popov N, Kenney AM, Schulte JH, Beijersbergen R, Christiansen H, Berwanger B, Eilers M (2009) Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell 15:67–78

    Article  CAS  PubMed  Google Scholar 

  12. Yang S, He S, Zhou X, Liu M, Zhu H, Wang Y, Zhang W, Yan S, Quan L, Bai J, Xu N (2010) Suppression of Aurora-A oncogenic potential by c-Myc downregulation. Exp Mol Med 42:759–767

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Sasayama T, Marumoto T, Kunitoku N, Zhang D, Tamaki N, Kohmura E, Saya H, Hirota T (2005) Over-expression of Aurora-A targets cytoplasmic polyadenylation element binding protein and promotes mRNA polyadenylation of Cdk1 and Cyclin B1. Genes Cells 10:627–638

    Article  CAS  PubMed  Google Scholar 

  14. 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 (2010) Aurora A is differentially expressed in gliomas, is associated with patient survival in glioblastoma and is a potential chemotherapeutic target in gliomas. Cell Cycle 11:489–502

    Article  Google Scholar 

  15. deCarvalho AC, Nelson K, Lemke N, Lehman NL, Arbab AS, Kalkanis S, Mikkelsen T (2010) Gliosarcoma stem cells undergo glial and mesenchymal differentiation in vivo. Stem Cells 28:181–190

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL, Black KL, Yu JS (2004) Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23:9392–9400

    Article  CAS  PubMed  Google Scholar 

  17. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64:7011–7021

    Article  CAS  PubMed  Google Scholar 

  18. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9:391–403

    Article  CAS  PubMed  Google Scholar 

  19. Lim SK, Gopalan G (2007) Aurora-A kinase interacting protein 1 (AURKAIP1) promotes Aurora-A degradation through an alternative ubiquitin-independent pathway. Biochem J 403:119–127

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Fumoto K, Lee PC, Saya H, Kikuchi A (2008) AIP regulates stability of Aurora-A at early mitotic phase coordinately with GSK-3beta. Oncogene 27:4478–4487

    Article  CAS  PubMed  Google Scholar 

  21. Qin L, Tong T, Song Y, Xue L, Fan F, Zhang G (2009) Aurora-A interacts with Cyclin B1 and enhances its stability. Cancer Lett 275:77–85

    Article  CAS  PubMed  Google Scholar 

  22. Asteriti IA, Rensen WM, Lindon C, Lavia P, Guarguaglini G (2010) The Aurora-A/TPX2 complex: a novel oncogenic holoenzyme? Biochim Biophys Acta 1806:230–239

    CAS  PubMed  Google Scholar 

  23. 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 (2012) Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells. J Cancer Res Clin Oncol 138:405–414

    Article  CAS  PubMed  Google Scholar 

  24. Venkataraman S, Alimova I, Tello T, Harris PS, Knipstein JA, Donson AM, Foreman NK, Liu AK, Vibhakar R (2012) Targeting Aurora kinase A enhances radiation sensitivity of atypical teratoid rhabdoid tumor cells. J Neurooncol 107:517–526

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Lisa J. Whitely for performing RT-PCR. This work was supported in part by NIH grant K08 NS45077 and in part by Takeda Pharmaceuticals International Co., which also supplied MLN8237. Coauthor Dr. Jeffrey A. Ecsedy is employed by Takeda. No other coauthors have a financial relationship with the company.

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Authors and Affiliations

  1. Departments of Pathology and Neuroscience, The Ohio State University, 4166 Graves Hall, 333 W. 10th Ave., Columbus, OH, 43210, USA

    James R. Van Brocklyn, Kahlil D. Barnett & Norman L. Lehman

  2. Department of Statistics, The Ohio State University, Columbus, OH, USA

    Dennis K. Pearl

  3. Department of Pathology, Henry Ford Hospital, Detroit, MI, USA

    James P. O’Donnell, Clarence R. Salazar & Norman L. Lehman

  4. Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA

    Xin Hong, Ana C. deCarvalho & Tom Mikkelsen

  5. Department of Radiation Oncology, Henry Ford Hospital, Detroit, MI, USA

    Stephen L. Brown

  6. Department of Oncology Translational Medicine, Takeda Pharmaceuticals International Co., Cambridge, MA, USA

    Jeffrey A. Ecsedy

Authors
  1. Xin Hong
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  2. James P. O’Donnell
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  3. Clarence R. Salazar
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  4. James R. Van Brocklyn
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  5. Kahlil D. Barnett
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  6. Dennis K. Pearl
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  7. Ana C. deCarvalho
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  8. Jeffrey A. Ecsedy
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  9. Stephen L. Brown
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  10. Tom Mikkelsen
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  11. Norman L. Lehman
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Corresponding author

Correspondence to Norman L. Lehman.

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Hong, X., O’Donnell, J.P., Salazar, C.R. et al. The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation. Cancer Chemother Pharmacol 73, 983–990 (2014). https://doi.org/10.1007/s00280-014-2430-z

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  • DOI: https://doi.org/10.1007/s00280-014-2430-z

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