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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / therapeutic use*
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Apoptosis / drug effects
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Brain / cytology
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Brain / metabolism
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Brain / pathology
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Brain / physiopathology
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Carrier Proteins / agonists*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Caspases / metabolism
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Enzyme Inhibitors / metabolism
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Flow Cytometry
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Glioma / drug therapy*
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Glioma / pathology
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Glioma / physiopathology
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Humans
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Intracellular Signaling Peptides and Proteins
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Ligands
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Membrane Glycoproteins / therapeutic use*
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Mice
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Mice, Nude
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Mitochondria / metabolism
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Mitochondrial Proteins / agonists*
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Neoplasm Transplantation
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Peptides / metabolism
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Peptides / pharmacology
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Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Remission Induction
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TNF-Related Apoptosis-Inducing Ligand
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Transplantation, Heterologous
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / therapeutic use*
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X-Linked Inhibitor of Apoptosis Protein
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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Carrier Proteins
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DIABLO protein, human
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Diablo protein, mouse
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Ligands
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Membrane Glycoproteins
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Mitochondrial Proteins
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Peptides
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Caspases