HDACi phenylbutyrate increases bystander killing of HSV-tk transfected glioma cells
Ole Ammerpohl1, Dorit Thormeyer, Zahidul Khan
1Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Abstract:
Malignant glioma patients have a dismal prognosis with an urgent need of new treatment modalities. Previously developed gene therapies for brain tumors showed promising results in experimental animal models, but failed in clinical trials due to low transfection rates and insufficient expression of the transgene in tumor cells, as well as low bystander killing effects. We have previously shown that the histone deacetylase inhibitor 4-phenylbutyrate (4-PB) enhances gap junction communication between glioma cells in culture. In this study, we demonstrate an activation of recombinant HSV-tk gene expression, and a dramatic enhancement of gap junction-mediated bystander killing effect by administration of the HSV-tk prodrug ganciclovir together with 4-PB. These findings that 4-PB potentiates "suicide gene" expression as well as enhances gap junctional communication and bystander killing of tumor cells justify further testing of this paradigm as an adjunct to suicide gene therapy of malignant gliomas.
Insights
Malignant glioma treatment faces challenges with gene therapy. This study shows 4-phenylbutyrate (4-PB) enhances suicide gene therapy by boosting gene expression and cell-to-cell communication for improved tumor cell killing.
Area of Science:
- Neuro-oncology
- Molecular Therapy
- Cancer Genetics
Background:
- Malignant gliomas have poor prognoses, necessitating novel treatments.
- Previous gene therapies for brain tumors faced clinical trial limitations, including low transfection and bystander effects.
Purpose of the Study:
- To investigate the efficacy of 4-phenylbutyrate (4-PB) in enhancing suicide gene therapy for malignant gliomas.
- To evaluate 4-PB's effect on recombinant HSV-tk gene expression and gap junction-mediated bystander killing.
Main Methods:
- Utilized 4-phenylbutyrate (4-PB), a histone deacetylase inhibitor.
- Administered the HSV-tk prodrug ganciclovir in conjunction with 4-PB.
- Assessed recombinant HSV-tk gene expression and gap junction communication.
Main Results:
- Demonstrated activation of recombinant HSV-tk gene expression with 4-PB administration.
- Showed a significant enhancement of gap junction-mediated bystander killing effect.
- 4-PB potentiated suicide gene expression and bystander killing in tumor cells.
Conclusions:
- 4-phenylbutyrate (4-PB) shows promise in augmenting suicide gene therapy for malignant gliomas.
- The combination of 4-PB with HSV-tk suicide gene therapy warrants further investigation.
- Enhanced gap junction communication and bystander killing represent a viable therapeutic strategy.
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