title: KAAD-cyclopamine augmented TRAIL-mediated apoptosis in malignant glioma cells by modulating the intrinsic and extrinsic apoptotic pathway.
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.
authors.affiliation: Department of Neuropathology, University Hospital Heidelberg, Germany. markus.siegelin@med.uni-heidelberg.de
authors.forename: Markus David
authors.initials: MD
authors.lastname: Siegelin
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Siegelin
authors.forename: Antje
authors.initials: A
authors.lastname: Habel
authors.forename: Abdelhaq
authors.initials: A
authors.lastname: Rami
authors.forename: Timo
authors.initials: T
authors.lastname: Gaiser
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014704:Veratrum Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C542465:3-keto-N-aminoethylaminoethylcaproyldihydrocinnamoyl cyclopamine; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002934:Cinnamates; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D014704:Veratrum Alkaloids; C000541:cyclopamine