17-AAG sensitized malignant glioma cells to death-receptor mediated apoptosis

Neurobiol Dis. 2009 Feb;33(2):243-9. doi: 10.1016/j.nbd.2008.10.005. Epub 2008 Nov 10.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Benzoquinones / administration & dosage
  • Benzoquinones / pharmacology*
  • Benzoquinones / therapeutic use
  • Blotting, Western
  • Brain / metabolism
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cytotoxins / therapeutic use
  • Drug Resistance, Neoplasm
  • Enzyme Activation / drug effects
  • Flow Cytometry
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Immunohistochemistry
  • Inhibitor of Apoptosis Proteins
  • Lactams, Macrocyclic / administration & dosage
  • Lactams, Macrocyclic / pharmacology*
  • Lactams, Macrocyclic / therapeutic use
  • Microtubule-Associated Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering
  • Survivin
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • TNF-Related Apoptosis-Inducing Ligand / therapeutic use

Substances

  • BIRC5 protein, human
  • Benzoquinones
  • Cytotoxins
  • HSP90 Heat-Shock Proteins
  • Inhibitor of Apoptosis Proteins
  • Lactams, Macrocyclic
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • Survivin
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • tanespimycin
  • Proto-Oncogene Proteins c-akt
  • Caspases