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Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo

Nature Medicine volume 8, pages 808–815 (2002)Cite this article

Abstract

A major concern in cancer therapy is resistance of tumors such as glioblastoma to current treatment protocols. Here, we report that transfer of the gene encoding second mitochondria-derived activator of caspase (Smac) or Smac peptides sensitized various tumor cells in vitro and malignant glioma cells in vivo for apoptosis induced by death-receptor ligation or cytotoxic drugs. Expression of a cytosolic active form of Smac or cell-permeable Smac peptides bypassed the Bcl-2 block, which prevented the release of Smac from mitochondria, and also sensitized resistant neuroblastoma or melanoma cells and patient-derived primary neuroblastoma cells ex vivo. Most importantly, Smac peptides strongly enhanced the antitumor activity of Apo-2L/tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in an intracranial malignant glioma xenograft model in vivo. Complete eradication of established tumors and survival of mice was only achieved upon combined treatment with Smac peptides and Apo2L/TRAIL without detectable toxicity to normal brain tissue. Thus, Smac agonists are promising candidates for cancer therapy by potentiating cytotoxic therapies.

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Figure 1: Overexpression of Smac sensitizes for death receptor– or drug-induced apoptosis.
Figure 2: Smac peptides sensitize for death receptor– or drug-induced apoptosis.
Figure 3: Smac peptides enhance the antitumor effect of TRAIL in a human glioma xenograft model in vivo.
Figure 4: Smac peptides do not reverse the lack of toxicity of TRAIL on normal human cells and normal brain tissue.
Figure 5: llustration of apoptosis pathways.

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Acknowledgements

We thank P.H. Krammer for anti-FLICE antibody; O. Hanemann for human primary Schwann cells; X. Wang and E. Alnemri for anti-Smac antibody and Smac cDNA; A. Ashkenazi for Apo2L/TRAIL.0; and P. Miller-Rostek for technical assistance. This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft, the Bundesministerium für Forschung and Technologie, the Wilhelm Sander-Stiftung and the European community.

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  1. Simone Fulda and Wolfgang Wick: S.F. and W.W. contributed equally to this study.

Authors and Affiliations

  1. University Children's Hospital, Ulm, Germany

    Simone Fulda & Klaus-Michael Debatin

  2. Department of Neurology, University of Tübingen, Tübingen, Germany

    Wolfgang Wick & Michael Weller

  3. Division of Molecular Oncology/Pediatrics, German Cancer Research Center, Heidelberg, Germany

    Klaus-Michael Debatin

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Correspondence to Klaus-Michael Debatin.

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Fulda, S., Wick, W., Weller, M. et al. Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8, 808–815 (2002). https://doi.org/10.1038/nm735

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