TRAIL enhances thymidine kinase/ganciclovir gene therapy of neuroblastoma cells
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Updated: Oct 1, 2026
Dual Bioluminescence Imaging of Tumor Progression and Angiogenesis
Published on: August 1, 2019
Christian Beltinger1, Simone Fulda, Henning Walczak
1University Children's Hospital, Ulm 89075, Germany. christian.beltinger@medizin.uni-ulm.de
Abstract:
The clinical benefit of suicide gene therapy of tumors has been marginal, mostly due to the low gene transfer efficiency in vivo. The death-inducing ligand, TRAIL, effectively kills many tumor cell types, while sparing most normal tissues. We hypothesized that TRAIL may enhance HSV thymidine kinase/ganciclovir (TK/GCV) gene therapy of tumor cells by augmenting both target and bystander cell kill. Human SH-EP neuroblastoma cells expressing TK as well as bystander cells were effectively killed by apoptosis, and their clonogenicity was ablated following GCV. Human TRAIL enhanced TK/GCV-induced cell death and decreased clonogenicity of TK-expressing cells and also of bystander cells. Cooperation between TRAIL and TK/GCV depended both on caspase activation and on mitochondrial apoptogenic function because both the broad-spectrum caspase inhibitor zVAD.fmk and overexpression of Bcl-2 decreased enhancement of cell kill by TRAIL. Facilitation of TRAIL signalling by up-regulation of TRAIL receptors did not contribute to enhancement because cell surface expression of the agonistic TRAIL receptors 1 and 2 was not increased by TK/GCV. In conclusion, the concerted activation of caspases and the mitochondrial amplification of caspase activation by TK/GCV may explain the cooperative effect of TK/GCV and TRAIL on the kill of neuroblastoma cells. Because combined treatment also augmented the bystander cell kill, the addition of TRAIL may increase the efficacy of TK/GCV gene therapy of neuroblastoma.
Insights
Adding TRAIL to herpes simplex virus thymidine kinase/ganciclovir (TK/GCV) gene therapy significantly enhances tumor cell killing and bystander effects in neuroblastoma. This combination therapy shows promise for improving treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Suicide gene therapy for tumors has limited clinical benefit due to low in vivo gene transfer efficiency.
- Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) effectively induces apoptosis in many tumor cells while sparing normal tissues.
- Herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) is a suicide gene therapy approach with potential for tumor cell killing.
Purpose of the Study:
- To investigate if TRAIL can enhance the efficacy of HSV-TK/GCV suicide gene therapy.
- To determine if TRAIL augments both direct tumor cell kill and bystander cell kill in neuroblastoma.
- To elucidate the mechanisms underlying the potential cooperative effect between TRAIL and TK/GCV therapy.
Main Methods:
- Utilized human SH-EP neuroblastoma cells expressing HSV-TK.
- Administered ganciclovir (GCV) to activate the TK/GCV system.
- Co-treated cells with human TRAIL and assessed cell death, apoptosis, and clonogenicity.
- Investigated the role of caspases and mitochondrial function using inhibitors (zVAD.fmk) and overexpression (Bcl-2).
- Analyzed TRAIL receptor expression levels on cell surfaces.
Main Results:
- GCV treatment of TK-expressing neuroblastoma cells induced apoptosis and reduced clonogenicity.
- Co-administration of TRAIL significantly enhanced TK/GCV-induced cell death and suppressed clonogenicity in both TK-expressing and bystander cells.
- The enhancement of cell kill by TRAIL was dependent on caspase activation and mitochondrial apoptotic pathways, as indicated by the effects of zVAD.fmk and Bcl-2.
- TK/GCV treatment did not upregulate cell surface expression of agonistic TRAIL receptors 1 and 2.
Conclusions:
- The combination of TRAIL and TK/GCV therapy demonstrates a cooperative effect on neuroblastoma cell killing.
- This synergy involves concerted caspase activation and mitochondrial amplification pathways.
- The enhanced bystander cell kill suggests that adding TRAIL to TK/GCV therapy could improve the overall efficacy of neuroblastoma treatment.
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