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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

Cancer Chemotherapy and Pharmacology volume 73, pages 983–990 (2014)Cite this article

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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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

Keywords

  • MLN8237
  • Alisertib
  • Glioblastoma
  • Neurospheres
  • Aurora-A
  • Temozolomide
  • Radiation