Pharmacological inhibition of Bcl-2 family members reactivates TRAIL-induced apoptosis in malignant glioma |
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Authors: | Holger Hetschko Valerie Voss Sigrid Horn Volker Seifert Jochen H M Prehn Donat Kögel |
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Institution: | Department of Neurosurgery, Centre for Neurology and Neurosurgery, Johann Wolfgang Goethe University Clinics, Theodor-Stern-Kai 7, Frankfurt/Main 60590, Germany. |
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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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Keywords: | Astrocytoma Apoptosis BH3 mimetic Death receptor TRAIL |
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