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Updated: Jun 7, 2025
Evaluating In Vitro DNA Damage Using Comet Assay
Published on: October 11, 2017
Olaparib Enhances the Efficacy of Third-Generation Oncolytic Adenoviruses Against Glioblastoma by Modulating DNA
Yida Liu1,2,3, Sheng Fang1,2,3, Peiwen Wang1,2,3
1Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
Aims:
Patients with glioblastoma multiforme (GBM) do not benefit from current cancer treatments, and their prognosis is dismal. This study aimed to investigate the potential synergistic effects of TS-2021, a third-generation oncolytic adenovirus, combined with the PARP inhibitor olaparib in GBM.
Methods:
TS-2021's impact on p66shc-induced apoptosis, DNA damage response, and poly (ADP-ribose) polymerase (PARP) activation was evaluated in GBM cells. The synergistic effect of TS-2021 and olaparib was examined in GBM cell lines and an immunocompetent mouse model of GBM. Mechanistic studies focused on the role of p66shc phosphorylation in the observed effects.
Results:
TS-2021 triggered p66shc-induced apoptosis, DNA damage response, and PARP activation. The combination of TS-2021 and olaparib synergistically increased cell apoptosis and DNA damage and reduced PARP expression compared to monotherapy. Olaparib promoted TS-2021 replication and release in GBM cells. Mechanistically, olaparib combined with TS-2021 upregulated p66shc phosphorylation, enhancing tumor cell apoptosis. In vivo, the combination therapy inhibited tumor growth and prolonged survival, confirming the synergistic effect.
Conclusion:
This study is the first to suggest that TS-2021 sensitizes GBM cells with wild-type BRCA1/2 to olaparib. The combination of TS-2021 and olaparib shows a synergistic therapeutic effect against GBM, providing a promising treatment strategy.
Insights
This study shows that combining TS-2021 oncolytic adenovirus with olaparib, a PARP inhibitor, offers a synergistic treatment for glioblastoma multiforme (GBM). This novel combination enhances apoptosis and DNA damage, improving outcomes for GBM patients.
Area of Science:
- Oncology
- Virology
- Genetics
Background:
- Glioblastoma multiforme (GBM) presents a dismal prognosis with limited treatment efficacy.
- Oncolytic viruses and PARP inhibitors are emerging therapeutic strategies for cancer.
Purpose of the Study:
- To investigate the synergistic effects of TS-2021 (oncolytic adenovirus) and olaparib (PARP inhibitor) in GBM.
- To explore the underlying mechanisms of this combination therapy.
Main Methods:
- Assessed TS-2021's effects on apoptosis, DNA damage, and PARP activation in GBM cells.
- Evaluated the synergistic efficacy of TS-2021 and olaparib in GBM cell lines and a mouse model.
- Investigated the role of p66shc phosphorylation in the therapeutic response.
Main Results:
- TS-2021 induced apoptosis, DNA damage, and PARP activation.
- The combination synergistically enhanced apoptosis and DNA damage while reducing PARP expression.
- Olaparib promoted TS-2021 replication, and the combination upregulated p66shc phosphorylation.
- In vivo studies demonstrated inhibited tumor growth and prolonged survival.
Conclusions:
- TS-2021 sensitizes GBM cells (wild-type BRCA1/2) to olaparib.
- The combination of TS-2021 and olaparib exhibits a synergistic therapeutic effect against GBM.
- This combination represents a promising new treatment strategy for glioblastoma.
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