Abstract
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic. The main obstacle in TRAIL-based therapy is that many glioma cells are resistant. In this study glioblastoma cell lines, human glioblastoma short-term cultures and human astrocytes were treated with 3-keto-N-aminoethylaminoethylcaproyldihydrocinnamoyl cyclopamine (KAAD-cyclopamine), tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) or the combination of both. Single treatment with KAAD-cyclopamine or TRAIL does not induce cytotoxicity in malignant glioma cells. However, treatment with KAAD-cyclopamine in combination with TRAIL induces rapid apoptosis in TRAIL-resistant glioma cells. Notably, normal human astrocytes were not affected by the combination treatment consisting of KAAD-cyclopamine and TRAIL. KAAD-cyclopamine led to an upregulation of death receptor 4 and 5 and down-regulation of bcl-2 and c-FLIP. Furthermore, overexpression of both bcl-2 and c-FLIP attenuated KAAD-cyclopamine facilitated TRAIL-mediated apoptosis. Taken together,we provided evidence that KAAD-cyclopamine facilitated TRAIL-mediated apoptosis at the level of the intrinsic and extrinsic apoptotic pathways in malignant glioma cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Apoptosis / drug effects*
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Apoptosis / physiology
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Apoptosis Regulatory Proteins / drug effects
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Apoptosis Regulatory Proteins / metabolism
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Astrocytes / drug effects
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Astrocytes / metabolism
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / metabolism
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Brain Neoplasms / physiopathology
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CASP8 and FADD-Like Apoptosis Regulating Protein / drug effects
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Cell Line, Tumor
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Cinnamates / pharmacology*
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Cinnamates / therapeutic use
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / physiology
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Glioma / drug therapy*
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Glioma / metabolism
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Glioma / physiopathology
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Humans
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Proto-Oncogene Proteins c-bcl-2 / drug effects
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / drug effects
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Receptors, Tumor Necrosis Factor / metabolism
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
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TNF-Related Apoptosis-Inducing Ligand / therapeutic use
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Up-Regulation / drug effects
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Up-Regulation / physiology
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Veratrum Alkaloids / pharmacology*
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Veratrum Alkaloids / therapeutic use
Substances
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3-keto-N-aminoethylaminoethylcaproyldihydrocinnamoyl cyclopamine
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Cinnamates
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Proto-Oncogene Proteins c-bcl-2
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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TNF-Related Apoptosis-Inducing Ligand
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TNFRSF10A protein, human
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TNFSF10 protein, human
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Veratrum Alkaloids
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cyclopamine