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17-AAG sensitized malignant glioma cells to death-receptor mediated apoptosis
Markus David Siegelin1, Antje Habel, Timo Gaiser
1Department of Neuropathology, University Hospital Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany. markus.siegelin@med.uni-heidelberg.de
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.
Insights
This study shows that combining 17-AAG with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively induces apoptosis in resistant glioma cells by down-regulating survivin. This combination therapy presents a promising strategy for treating malignant gliomas.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastoma is an aggressive brain tumor with limited treatment options.
- Heat shock protein 90 (HSP90) inhibitors, like 17-AAG, show therapeutic potential in cancer.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic cytokine with potential anti-cancer activity.
Purpose of the Study:
- To investigate the efficacy of combining 17-AAG and TRAIL in glioblastoma treatment.
- To elucidate the role of survivin in the combined treatment's mechanism of action.
Main Methods:
- Treatment of three glioblastoma cell lines (U87, LN229, U251) with 17-AAG, TRAIL, or both.
- Analysis of apoptosis induction and survivin levels.
- Assessment of survivin's role via overexpression studies.
Main Results:
- Subtoxic doses of 17-AAG combined with TRAIL induced rapid apoptosis in TRAIL-resistant glioma cells.
- 17-AAG treatment led to survivin down-regulation via proteasomal degradation.
- Overexpression of survivin attenuated the cytotoxic effects of the combined 17-AAG and TRAIL treatment.
Conclusions:
- The combination of 17-AAG and TRAIL is a potent strategy for inducing apoptosis in malignant glioma cells.
- Survivin is a critical regulator of cell death induced by the combined 17-AAG and TRAIL therapy.
- This combined approach offers a promising therapeutic avenue for gliomas.