Abstract
Embelin has been reported to exhibit therapeutic activity in cancer. In this study glioblastoma cells and human astrocytes were treated with Embelin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the combination of both. Treatment with subtoxic doses of Embelin broadly sensitized malignant glioma cells to TRAIL-mediated apoptosis. Notably, human astrocytes were not significantly affected by the combined treatment consisting of Embelin and TRAIL. Combined treatment with Embelin and TRAIL augmented the activation of initiator caspases-8/-9 and effector caspases-3/-7, respectively. Furthermore, Embelin down-regulated the expression of the long- and short-isoform of c-FLIP. In addition, forced expression of the short isoform of c-FLIP (S) attenuated apoptosis induced by the combination of Embelin and TRAIL. Embelin did not modulate the mRNA levels of c-FLIP (S), suggesting that Embelin modulates the expression of c-FLIP in a posttranscriptional manner. In summary, the short isoform of c-FLIP is a key regulator in TRAIL-Embelin-mediated apoptosis in malignant glioma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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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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Benzoquinones / pharmacology*
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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 / antagonists & inhibitors*
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Cell Line
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Cell Line, Tumor
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Drug Synergism
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / 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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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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TNF-Related Apoptosis-Inducing Ligand / agonists*
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X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors
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X-Linked Inhibitor of Apoptosis Protein / metabolism
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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Benzoquinones
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Protein Isoforms
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RNA, Messenger
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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embelin