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

Xin Hong, James P. O'Donnell, Clarence R. Salazar, James R. Van Brocklyn, Kahlil D. Barnett, Dennis K. Pearl, Ana C. DeCarvalho, Jeffrey A. Ecsedy, Stephen L. Brown, Tom Mikkelsen, Norman L. Lehman

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)983-990
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume73
Issue number5
DOIs
StatePublished - May 2014

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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