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

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.
Authors	Simone Fulda, Wolfgang Wick, Michael Weller, Klaus-Michael Debatin
Journal	Nature medicine (Nat Med) Vol. 8 Issue 8 Pg. 808-15 (Aug 2002) ISSN: 1078-8956 [Print] United States
PMID	12118245 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Apoptosis Regulatory Proteins Carrier Proteins DIABLO protein, human Diablo protein, mouse Enzyme Inhibitors Intracellular Signaling Peptides and Proteins Ligands Membrane Glycoproteins Mitochondrial Proteins Peptides Proteins Proto-Oncogene Proteins c-bcl-2 TNF-Related Apoptosis-Inducing Ligand TNFSF10 protein, human Tnfsf10 protein, mouse Tumor Necrosis Factor-alpha X-Linked Inhibitor of Apoptosis Protein XIAP protein, human Caspases
Topics	Animals Antineoplastic Agents (metabolism, therapeutic use) Apoptosis (drug effects, physiology) Apoptosis Regulatory Proteins Brain (cytology, metabolism, pathology, physiopathology) Carrier Proteins (agonists, genetics, metabolism) Caspases (metabolism) Enzyme Inhibitors (metabolism) Flow Cytometry Glioma (drug therapy, pathology, physiopathology) Humans Intracellular Signaling Peptides and Proteins Ligands Membrane Glycoproteins (therapeutic use) Mice Mice, Nude Mitochondria (metabolism) Mitochondrial Proteins (agonists, genetics, metabolism) Neoplasm Transplantation Peptides (metabolism, pharmacology) Proteins (metabolism) Proto-Oncogene Proteins c-bcl-2 (metabolism) Remission Induction TNF-Related Apoptosis-Inducing Ligand Transplantation, Heterologous Tumor Cells, Cultured Tumor Necrosis Factor-alpha (therapeutic use) X-Linked Inhibitor of Apoptosis Protein

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