17-AAG sensitized malignant glioma cells to death-receptor mediated apoptosis.
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.
Siegelin
Markus David
MD
Department of Neuropathology, University Hospital Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany. markus.siegelin@med.uni-heidelberg.de
Habel
Antje
A
Gaiser
Timo
T
D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology* / Q000627:therapeutic use
C107489:BIRC5 protein, human; D016227:Benzoquinones; D003603:Cytotoxins; D018841:HSP90 Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D047029:Lactams, Macrocyclic; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C112765:tanespimycin; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases