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Pharmacological inhibition of Bcl-2 family members reactivates TRAIL-induced apoptosis in malignant glioma

  • Lab Investigation - human/animal tissue
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Abstract

The major aim of this study was to develop novel therapeutic approaches to potentiate and reactivate apoptosis induced by TNF-Related Apoptosis Inducing Ligand (TRAIL) in malignant glioma. Analysis of five glioma cell lines (U87, U251, U373, MZ-54 and MZ-18) indicated that only two of the cell lines were sensitive to apoptosis induced by TRAIL alone. TRAIL resistance was not correlated to expression levels of the death receptors DR4 and DR5 or the decoy receptors DcR1 and DcR2, suggesting that it was mediated by inactivation of TRAIL-induced downstream signalling. Activation of the BH3 only protein Bid and subsequent activation of the mitochondrial apoptosis pathway are known to play a pivotal role in TRAIL-induced apoptosis. Since this process is blocked by overexpression of anti-apoptotic Bcl-2 family members, we analyzed the therapeutic potential of BH3 mimetics in potentiating TRAIL-induced apoptosis. Treatment with TRAIL in combination with the specific Bcl-2 inhibitor HA14-1 and the Bcl-2/Bcl-xL inhibitor BH3I-2′ potently enhanced apoptosis in TRAIL-sensitive U87 cells in a dose-dependent fashion. TRAIL-induced apoptosis was significantly reactivated by HA14-1 and BH3I-2′ in one (U343) and two (MZ-54 and MZ-18) of three investigated TRAIL-insensitive cell lines, respectively. Knockdown of the anti-apoptotic Bcl-2 family member Mcl-1 by RNA interference had no additional effect on apoptosis induced by TRAIL and HA14-1 in U87 and U343 cells. Our data indicate that Bcl-2 and Bcl-xL play fundamental roles in TRAIL resistance of malignant glioma and suggest that using TRAIL or agonistic TRAIL receptor antibodies in combination with BH3 mimetics may represent a promising approach to reactivate apoptosis in therapy-resistant high grade gliomas.

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Abbreviations

DMSO:

Dimethyl sulfoxide

DR4:

Death receptor 4

DR5:

Death receptor 5

TRAIL:

Tumor necrosis factor related apoptosis inducing ligand

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Acknowledgements

The authors would like to thank Hildegard Schweers and Monika Herr for excellent technical assistance. This study was supported by the Wilhelm Sander Stiftung (grant 2005.067.1) to DK and by Science Foundation Ireland to JHMP.

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Authors and Affiliations

  1. Department of Neurosurgery, Centre for Neurology and Neurosurgery, Johann Wolfgang Goethe University Clinics, Theodor-Stern-Kai 7, Frankfurt/Main, 60590, Germany

    Holger Hetschko, Valerie Voss, Volker Seifert & Donat Kögel

  2. Department of Neurosurgery, Johannes Gutenberg University Clinics, Langenbeckstraße 1, Mainz, 55101, Germany

    Sigrid Horn

  3. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2, Ireland

    Jochen H. M. Prehn

Authors
  1. Holger Hetschko
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  2. Valerie Voss
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  3. Sigrid Horn
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  4. Volker Seifert
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  5. Jochen H. M. Prehn
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  6. Donat Kögel
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Correspondence to Donat Kögel.

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Hetschko, H., Voss, V., Horn, S. et al. Pharmacological inhibition of Bcl-2 family members reactivates TRAIL-induced apoptosis in malignant glioma. J Neurooncol 86, 265–272 (2008). https://doi.org/10.1007/s11060-007-9472-6

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  • DOI: https://doi.org/10.1007/s11060-007-9472-6

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