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Adenovirus-mediated transfer of caspase-8 augments cell death in gliomas: implication for gene therapy
N Shinoura1, H Koike, T Furitu
1Department of Molecular Biotherapy Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Abstract:
Caspase-8 is a member of the family of caspases, which are involved in the execution of apoptosis. To investigate whether caspase-8 can be used for gene therapy of gliomas, we transduced A-172 and U251 glioma cells with the caspase-8 gene via an adenoviral vector (Adv) controlled by the chicken beta-actin (CA) promoter (Advcaspase-8), and found that a similar level of caspase-8 protein induced A-172 cells to undergo necrotic cell death and U251 cells to undergo apoptotic cell death. Neither Bcl-XL nor Bcl-2, which play important roles in antiapoptotic mechanisms in gliomas, protected glioma cells from apoptosis induced by overexpression of caspase-8. Injection of Adv-caspase-8 suppressed the in vivo growth of U251 xenografts, in which apoptotic cell death remarkably increased as revealed by TUNEL analysis. Finally, we assessed whether gene therapy with a tissue-specific promoter, the myelin basic protein (MBP) promoter, is applicable to gliomas. Adv for caspase-8 controlled by the MBP promoter induced drastic apoptosis in U251 and U-373MG glioma cells, whereas it did not induce apoptosis in human endothelial cells, fibroblasts, and nerve growth factor-treated PC12 cells. These results indicate that Adv for caspase-8 effectively induced cell death in gliomas, and that this approach may be a useful modality for gene therapy of gliomas.
Insights
Gene therapy using caspase-8 (an apoptosis-executing protein) effectively induced cell death in glioma cells. This approach shows promise for treating gliomas, even when anti-apoptotic mechanisms are present.
Area of Science:
- Molecular Biology
- Oncology
- Gene Therapy
Background:
- Caspase-8 is crucial for apoptosis execution.
- Gliomas possess anti-apoptotic mechanisms (Bcl-XL, Bcl-2) that hinder treatment.
- Gene therapy offers a potential strategy for targeting cancer cells.
Purpose of the Study:
- To investigate the potential of caspase-8 gene therapy for gliomas.
- To evaluate the efficacy of adenoviral vector-mediated caspase-8 delivery.
- To assess the use of tissue-specific promoters for glioma targeting.
Main Methods:
- Transduction of glioma cell lines (A-172, U251) with adenoviral vectors expressing caspase-8 (Advcaspase-8).
- Assessment of cell death (apoptosis and necrosis) and protein expression.
- In vivo studies using U251 xenografts and TUNEL analysis.
- Evaluation of tissue-specific promoters (e.g., MBP promoter) for targeted gene delivery.
Main Results:
- Advcaspase-8 induced both necrotic and apoptotic cell death in glioma cells.
- Overexpressed caspase-8 effectively induced apoptosis, unaffected by Bcl-XL or Bcl-2.
- Advcaspase-8 suppressed U251 xenograft growth in vivo, with increased apoptosis.
- MBP promoter-driven Advcaspase-8 selectively induced apoptosis in glioma cells, sparing normal cells.
Conclusions:
- Adenoviral delivery of caspase-8 is effective in inducing glioma cell death.
- Caspase-8 gene therapy can overcome glioma's anti-apoptotic defenses.
- Tissue-specific promoters enhance the safety and efficacy of caspase-8 gene therapy for gliomas.
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