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Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells

Journal of Cancer Research and Clinical Oncology volume 138, pages 405–414 (2012)Cite this article

Abstract

Background

Glioblastoma remains one of the most devastating human malignancies, and despite therapeutic advances, there are no drugs that significantly improve the patient survival. Altered expression of the Aurora kinases was found in different malignancies, and their inhibition has been studied in cancer therapy. In this study, we analyzed the expression of Aurora A and Aurora B in glioblastoma samples and also analyzed whether the effects of Aurora kinase inhibition were associated with temozolomide or not on cell lines and primary cultures of glioblastoma.

Materials and methods

RT-PCR assays were used to determine the mRNA expression in glioblastoma tumor samples and in the cell lines. Cell proliferation was measured by XTT assay, and apoptosis was determined by flow cytometry. Drug combination analyses were made based in Chou-Talalay method. Gamma radiation for clonogenic survival used the doses of 2, 4 and 6 Gy. Changes in Aurora B level were assessed by Western blot analysis.

Results

Aurora A and B were expressed in glioblastoma samples as well as in the glioblastoma cell lines (n = 6). Moreover, ZM447439, a selective Aurora kinase inhibitor, decreased the proliferation separately and synergistically with temozolomide in primary cultures and cell lines of glioblastoma. ZM also enhanced the effects of radiation on the two cell lines studied (U343 and U251), mainly when associated with TMZ in U343 cells. Treatment with ZM induced apoptotic cell death and diminished Aurora B protein level.

Conclusions

These data suggest that Aurora kinase inhibition may be a target for glioblastoma treatment and could be used as adjuvant to chemo- and radiotherapy.

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Acknowledgments

We would like to thank Patrícia Vianna Bonini Palma, Camila Cristina de Oliveira Menezes Bonaldo and Daiane Fernanda dos Santos, Hemocentro-FMRP-USP, Ribeirão Preto, Brazil, for their assistance with the flow cytometry. Financial Support from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, process number 2009/50118-2), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior and Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo is acknowledged.

Conflict of interest

The authors declare that they have no conflict of interest.

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Affiliations

  1. Department of Genetics, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Avenida Bandeirantes 3900, Ribeirão Preto, SP, 14048-900, Brazil

    Kleiton Silva Borges, Angel Maurício Castro-Gamero, Daniel Antunes Moreno & Luiz Gonzaga Tone

  2. Department of Pediatrics, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, Brazil

    Vanessa da Silva Silveira, Maria Sol Brassesco, Rosane Gomes de Paula Queiroz, Carlos Alberto Scrideli & Luiz Gonzaga Tone

  3. Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, Brazil

    Harley Francisco de Oliveira

  4. Department of Surgery and Anatomy, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, Brazil

    Carlos Gilberto Carlotti Jr.

Authors
  1. Kleiton Silva Borges
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  2. Angel Maurício Castro-Gamero
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  3. Daniel Antunes Moreno
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  4. Vanessa da Silva Silveira
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  5. Maria Sol Brassesco
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  6. Rosane Gomes de Paula Queiroz
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  7. Harley Francisco de Oliveira
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  8. Carlos Gilberto Carlotti Jr.
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  9. Carlos Alberto Scrideli
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  10. Luiz Gonzaga Tone
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Correspondence to Kleiton Silva Borges.

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Borges, K.S., Castro-Gamero, A.M., Moreno, D.A. et al. Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells. J Cancer Res Clin Oncol 138, 405–414 (2012). https://doi.org/10.1007/s00432-011-1111-0

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  • DOI: https://doi.org/10.1007/s00432-011-1111-0

Keywords

  • Glioblastoma
  • Aurora A
  • Aurora B
  • ZM447439
  • Temozolomide
  • Radiation