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Dexamethasone inhibits the HSV-tk/ ganciclovir bystander effect in malignant glioma cells
Pierre A Robe1, Minh Nguyen-Khac, Olivier Jolois
1Department of Neurosurgery, University of Liège, Liège, Belgium. pierre.robe@ulg.ac.be
Background:
HSV-tk/ ganciclovir (GCV) gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate any significant benefit of this strategy in the treatment of human brain tumors. Since dexamethasone is a frequently used symptomatic treatment for malignant gliomas, its interaction with the bystander effect and the overall efficacy of HSV-TK gene therapy ought to be assessed.
Methods:
Stable clones of TK-expressing U87, C6 and LN18 cells were generated and their bystander effect on wild type cells was assessed. The effects of dexamethasone on cell proliferation and sensitivity to ganciclovir were assessed with a thymidine incorporation assay and a MTT test. Gap junction mediated intercellular communication was assessed with microinjections and FACS analysis of calcein transfer. The effect of dexamethasone treatment on the sensitivity of TK-expressing to FAS-dependent apoptosis in the presence or absence of ganciclovir was assessed with an MTT test. Western blot was used to evidence the effect of dexamethasone on the expression of Cx43, CD95, CIAP2 and BclXL.
Results:
Dexamethasone significantly reduced the bystander effect in TK-expressing C6, LN18 and U87 cells. This inhibition results from a reduction of the gap junction mediated intercellular communication of these cells (GJIC), from an inhibition of their growth and thymidine incorporation and from a modulation of the apoptotic cascade.
Conclusion:
The overall efficacy of HSV-TK gene therapy is adversely affected by dexamethasone co-treatment in vitro. Future HSV-tk/ GCV gene therapy clinical protocols for gliomas should address this interference of corticosteroid treatment.
Insights
Dexamethasone significantly reduces the bystander effect in HSV-tk/ganciclovir gene therapy for brain tumors by inhibiting cell communication and growth. This interference negatively impacts gene therapy efficacy, requiring consideration in future clinical protocols for gliomas.
Area of Science:
- Oncology
- Gene Therapy
- Cell Biology
Background:
- Herpes simplex virus thymidine kinase (HSV-tk) combined with ganciclovir (GCV) gene therapy is a studied brain tumor treatment relying on the bystander effect.
- Previous large studies have not shown significant benefits for HSV-tk/GCV gene therapy in human brain tumors.
- Dexamethasone is a common glioma treatment, necessitating an evaluation of its interaction with the bystander effect and overall gene therapy efficacy.
Purpose of the Study:
- To assess the impact of dexamethasone on the bystander effect of HSV-tk gene therapy in glioma cells.
- To investigate the mechanisms by which dexamethasone influences HSV-tk/GCV gene therapy efficacy.
- To determine if dexamethasone co-treatment affects glioma cell sensitivity to GCV and apoptosis.
Main Methods:
- Generated stable HSV-tk expressing glioma cell lines (U87, C6, LN18).
- Assessed bystander effect, cell proliferation, and GCV sensitivity using thymidine incorporation and MTT assays.
- Evaluated gap junction intercellular communication (GJIC) via microinjections and calcein transfer.
- Analyzed dexamethasone's effect on FAS-dependent apoptosis and expression of key proteins (Cx43, CD95, CIAP2, BclXL) using Western blot.
Main Results:
- Dexamethasone significantly reduced the bystander effect in all tested HSV-tk expressing glioma cell lines.
- This inhibition was attributed to decreased GJIC, reduced cell proliferation and thymidine incorporation, and modulation of the apoptotic cascade.
- Dexamethasone altered the expression of proteins involved in cell communication and apoptosis.
Conclusions:
- Dexamethasone co-treatment adversely affects the in vitro efficacy of HSV-tk/GCV gene therapy for gliomas.
- Future clinical protocols for HSV-tk/GCV gene therapy in gliomas must account for the interference by corticosteroid treatments like dexamethasone.
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