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Journal of Neuro-Oncology

, Volume 137, Issue 3, pp 481–492 | Cite as

The CNS penetrating taxane TPI 287 and the AURKA inhibitor alisertib induce synergistic apoptosis in glioblastoma cells

  • Cory T. Zumbar
  • Aisulu Usubalieva
  • Paul D. King
  • Xiaohui Li
  • Caroline S. Mifsud
  • Hailey M. Dalton
  • Muge Sak
  • Sara Urio
  • William M. Bryant
  • Joseph P. McElroy
  • George Farmer
  • Norman L. LehmanEmail author
Laboratory Investigation

Abstract

Glioblastoma is a highly malignant disease in critical need of expanded treatment options. The AURKA inhibitor alisertib exhibits antiproliferative activity against glioblastoma in vitro and in vivo. Unlike current clinically used taxane drugs, the novel taxane TPI 287 penetrates the CNS. We tested for interactions between three selective AURKA inhibitors and TPI 287 against standard U87 and U1242 cells and primary glioblastoma neurospheres using colony formation assays. Bliss and Chou–Talalay analyses were utilized to statistically test for synergism. Morphological analysis, flow cytometry and annexin V binding were employed to examine cell cycle and apoptotic effects of these drug combinations. TPI 287 not only potentiated the cytotoxicity of the AURKA inhibitors alisertib, MLN8054 and TC-A2317, but was often potently synergistic. Morphologic and biochemical analysis of the combined effects of alisertib and TPI 287 consistently revealed synergistic induction of apoptosis. While each agent alone induces a mitotic block, slippage occurs allowing some tumor cells to avoid apoptosis. Combination treatment greatly attenuated mitotic slippage, committing the majority of cells to apoptosis. Alisertib and TPI 287 demonstrate significant synergism against glioblastoma cells largely attributable to a synergistic effect in inducing apoptosis. These results provide compelling rationale for clinical testing of alisertib and/or other AURKA inhibitors for potential combination use with TPI 287 against glioblastoma and other CNS neoplasms.

Keywords

TPI 287 Alisertib Apoptosis Synergy Glioblastoma 

Notes

Acknowledgements

Funding for this work was supported by NIH Grant RO1 NS081125 (NLL).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

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Supplementary material 1 (EPS 1380 KB)
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Supplementary material 2 (EPS 2014 KB)
11060_2018_2755_MOESM3_ESM.docx (17 kb)
Supplementary material 3 (DOCX 17 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Cory T. Zumbar
    • 1
    • 2
  • Aisulu Usubalieva
    • 3
  • Paul D. King
    • 3
  • Xiaohui Li
    • 3
  • Caroline S. Mifsud
    • 3
  • Hailey M. Dalton
    • 3
  • Muge Sak
    • 1
    • 2
  • Sara Urio
    • 3
  • William M. Bryant
    • 3
  • Joseph P. McElroy
    • 5
  • George Farmer
    • 6
  • Norman L. Lehman
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Department of Pathology and Laboratory MedicineUniversity of LouisvilleLouisvilleUSA
  2. 2.James Graham Brown Cancer CenterLouisvilleUSA
  3. 3.Department of PathologyOhio State UniversityColumbusUSA
  4. 4.Department of NeuroscienceOhio State UniversityColumbusUSA
  5. 5.Department of Biomedical InformaticsOhio State UniversityColumbusUSA
  6. 6.Cortice Biosciences, IncNew YorkUSA

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