Abstract
17-AAG is a selective HSP90-inhibitor that exhibited therapeutic activity in cancer. In this study three glioblastoma cell lines (U87, LN229 and U251) were treated with 17-AAG, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the combination of both. Treatment with subtoxic doses of 17-AAG in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rapid apoptosis in TRAIL-resistant glioma cells, suggesting that this combined treatment may offer an attractive strategy for treating gliomas. 17-AAG treatment down-regulated survivin through proteasomal degradation. In addition, over-expression of survivin attenuated cytotoxicity induced by the combination of 17-AAG and TRAIL. In summary, survivin is a key regulator of TRAIL-17-AAG mediated cell death in malignant glioma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Benzoquinones / administration & dosage
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Benzoquinones / pharmacology*
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Benzoquinones / therapeutic use
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Blotting, Western
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Brain / metabolism
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Caspases / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Cytotoxins / therapeutic use
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Drug Resistance, Neoplasm
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Enzyme Activation / drug effects
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Flow Cytometry
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Glioblastoma / drug therapy
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Glioblastoma / metabolism
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Glioblastoma / pathology*
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Immunohistochemistry
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Inhibitor of Apoptosis Proteins
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Lactams, Macrocyclic / administration & dosage
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Lactams, Macrocyclic / pharmacology*
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Lactams, Macrocyclic / therapeutic use
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Microtubule-Associated Proteins / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering
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Survivin
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
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TNF-Related Apoptosis-Inducing Ligand / therapeutic use
Substances
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BIRC5 protein, human
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Benzoquinones
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Cytotoxins
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HSP90 Heat-Shock Proteins
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Inhibitor of Apoptosis Proteins
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Lactams, Macrocyclic
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Microtubule-Associated Proteins
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RNA, Small Interfering
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Survivin
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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tanespimycin
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Proto-Oncogene Proteins c-akt
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Caspases