APO010, a synthetic hexameric CD95 ligand, induces human glioma cell death in vitro and in vivo

Death receptor targeting has emerged as one of the promising novel approaches of cancer therapy. The activation of one such prototypic death receptor, CD95 (Fas/APO-1), has remained controversial because CD95 agonistic molecules have exhibited either too strong toxicity or too little activity. The n...

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Bibliographic Details
Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2011-02, Vol.13 (2), p.155-164
Main Authors: Eisele, Günter, Roth, Patrick, Hasenbach, Kathy, Aulwurm, Steffen, Wolpert, Fabian, Tabatabai, Ghazaleh, Wick, Wolfgang, Weller, Michael
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Basic and Translational Investigations
Blotting, Western
Brain Neoplasms - metabolism
Brain Neoplasms - pathology
Brain Neoplasms - prevention & control
Cell Proliferation - drug effects
Fas Ligand Protein - immunology
Fas Ligand Protein - pharmacology
fas Receptor - agonists
fas Receptor - metabolism
Flow Cytometry
Glioma - metabolism
Glioma - pathology
Glioma - prevention & control
Humans
Immunoenzyme Techniques
In Vitro Techniques
Mice
Recombinant Fusion Proteins - immunology
Recombinant Fusion Proteins - pharmacology
Tumor Cells, Cultured
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Summary:Death receptor targeting has emerged as one of the promising novel approaches of cancer therapy. The activation of one such prototypic death receptor, CD95 (Fas/APO-1), has remained controversial because CD95 agonistic molecules have exhibited either too strong toxicity or too little activity. The natural CD95 ligand (CD95L) is a cytokine, which needs to trimerize to mediate a cell death signal. Mega-Fas-Ligand, now referred to as APO010, is a synthetic hexameric CD95 agonist that exhibits strong antitumor activity in various tumor models. Here, we studied the effects of APO010 in human glioma models in vitro and in vivo. Compared with a cross-linked soluble CD95L or a CD95-agonistic antibody, APO010 exhibited superior activity in glioma cell lines expressing CD95 and triggered caspase-dependent cell death. APO010 reduced glioma cell viability in synergy when combined with temozolomide. The locoregional administration of APO010 induced glioma cell death in vivo and prolonged the survival of tumor-bearing mice. A further exploration of APO010 as a novel antiglioma agent is warranted.
ISSN:1522-8517
1523-5866
DOI:10.1093/neuonc/noq176