b2-Adrenergic receptor agonist enhances the bystander effect of HSV-TK/GCV gene therapy in glioblastoma multiforme via upregulation of connexin 43 expression

Molecular Therapy: Oncolytics, 2022 · DOI: https://doi.org/10.1016/j.omto.2022.05.010 · Published: September 1, 2022

Simple Explanation

Glioblastoma multiforme (GBM) is a highly invasive brain tumor. Gene therapy using HSV-TK/GCV is a potential treatment, but its effectiveness is limited by poor communication between tumor cells. This study explores whether enhancing this communication can improve the therapy's impact. The research focuses on connexin 43 (Cx43), a protein crucial for cell communication. The study investigates if a drug called clenbuterol hydrochloride (Cln), which increases Cx43 levels, can improve the effectiveness of HSV-TK/GCV gene therapy. The study found that Cln increased Cx43 expression in GBM cells and improved the killing effect of GCV. This suggests that Cln could enhance gene therapy for GBM by improving communication between tumor cells and promoting cell death.

Study Duration

Not specified

Participants

GBM tissue samples from patients who underwent surgical resection

Evidence Level

Not specified

Key Findings

1
Cln upregulated Cx43 expression in human GBM cells and OECs.
2
Cln promoted the cytotoxic effect of GCV on the co-culture cells.
3
Cln increased apoptosis in the co-culture of GBM cells and OEC-TK cells.

Research Summary

This study investigated the effect of Cln, a b2-adrenergic receptor agonist, on the bystander effect of HSV-TK/GCV gene therapy in human GBM cells using OECs as vectors. The researchers found that Cln upregulated Cx43 expression in GBM cells and OECs and promoted the cytotoxic effect of GCV. The study also showed that Cln increased cleaved caspase-3 expression and the Bax/Bcl2 ratio, indicating increased apoptosis. Flow cytometry results confirmed that Cln increased apoptosis in the co-culture of GBM cells and OEC-TK cells. The authors concluded that Cln, via upregulation of Cx43 expression, enhances the bystander effect of HSVTK-GCV gene therapy in human GBM cells, suggesting a potential strategy to improve GBM treatment.

Practical Implications

Improved GBM Therapy

Cln, by increasing Cx43 expression and enhancing GJIC, can be a valuable adjunct to HSV-TK/GCV gene therapy for GBM.

Targeting b2-AR

The b2-AR pathway can be targeted to modulate Cx43 expression and improve the efficacy of gene therapies in cancer.

Enhanced Bystander Effect

Upregulation of Cx43 expression may gate accessibility of cytotoxic metabolite to deeper layers of GBM.

Study Limitations

1
The study was performed on primary cells isolated from GBM tumors; results can be relatively generalized to whole human GBM tissue.
2
Additional b2-AR agonists and antagonists should be studied to examine the effect of b2-AR on Cx43 expression and HSV-TK/GCV gene therapy.
3
In vitro studies do not examine the effects of the microenvironment of the tumors and the roles of the immune system, angiogenesis, and other cells of the tumor microenvironment.

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