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Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins

Oncogene volume 27, pages 6646–6656 (2008)Cite this article

Abstract

Defects in the apoptotic signaling cascades contribute to the poor therapeutic response of malignant gliomas. As glioblastomas are characterized by high expression levels of anti-apoptotic Bcl-2 family proteins, we studied the effects of the novel Bcl-2 inhibitor, ABT-737, on malignant glioma cells. ABT-737 treatment released the pro-apoptotic Bax protein from its binding partner Bcl-2 and potently induced apoptotic cell death in glioblastoma cells in vitro and in vivo. The local administration of ABT-737 prolonged the survival in an intracranial glioma xenograft model. Downregulation of Mcl-1 and overexpression of Bcl-2 sensitized the cells to ABT-737-mediated apoptosis. Moreover, ABT-737 potentiated the cytotoxicity of the chemotherapeutic drugs vincristine and etoposide, and of the death ligand TRAIL. As glioma stem cells may play a crucial role for the tumor progression and the resistance to treatment in glioblastomas, we investigated the effects of ABT-737 on the subpopulation of glioma cells exhibiting stem cell characteristics. Inhibition of proliferation and induction of apoptosis by ABT-737 were less efficient in glioma stem cells than in non-stem cell-like glioma cells. As the resistance of glioma stem cells was associated with high Mcl-1 expression levels, ABT-737 treatment combined with downregulation of Mcl-1 could represent a promising novel approach in glioblastoma treatment.

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Acknowledgements

This work was supported by a grant from the Deutsche Krebshilfe to WR (German Cancer Aid, Max Eder Program). We thank Ilona Demir, Monika Frank-Stöhr and Sarah Meßnard for expert technical assistance. We thank Manfred Jugold (Molecular Imaging, German Cancer Research Center) for performing magnetic resonance imaging of animals.

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Authors and Affiliations

  1. Molecular Neuro-Oncology, German Cancer Research Center, Heidelberg, Germany

    K E Tagscherer, A Fassl, A Kraemer, B C Böck, O D Wiestler & W Roth

  2. Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany

    B Campos, M Farhadi & C Herold-Mende

  3. Institute of Pathology, University of Heidelberg, Heidelberg, Germany

    S Macher-Goeppinger & W Roth

  4. Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany

    B Radlwimmer

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  1. K E Tagscherer
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  2. A Fassl
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  3. B Campos
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  4. M Farhadi
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Correspondence to W Roth.

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Tagscherer, K., Fassl, A., Campos, B. et al. Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins. Oncogene 27, 6646–6656 (2008). https://doi.org/10.1038/onc.2008.259

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