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奥拉帕利通过调节 DNA 损伤反应和 p66shc 诱导的细胞凋亡增强第三代溶瘤腺病毒治疗胶质母细胞瘤的疗效。

Olaparib Enhances the Efficacy of Third-Generation Oncolytic Adenoviruses Against Glioblastoma by Modulating DNA Damage Response and p66shc-Induced Apoptosis.

机构信息

Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.

Department of Neurosurgery, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing, China.

出版信息

CNS Neurosci Ther. 2024 Nov;30(11):e70124. doi: 10.1111/cns.70124.

DOI:10.1111/cns.70124
PMID:39552450
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11570871/
Abstract

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.

摘要

目的

多形性胶质母细胞瘤（GBM）患者不能从当前的癌症治疗中获益，其预后较差。本研究旨在探讨第三代溶瘤腺病毒 TS-2021 联合 PARP 抑制剂奥拉帕利治疗 GBM 的潜在协同作用。

方法

评估了 TS-2021 对 GBM 细胞中 p66shc 诱导的细胞凋亡、DNA 损伤反应和聚（ADP-核糖）聚合酶（PARP）激活的影响。在 GBM 细胞系和免疫功能正常的 GBM 小鼠模型中研究了 TS-2021 和奥拉帕利的协同作用。机制研究集中在观察到的效应中 p66shc 磷酸化的作用。

结果

TS-2021 触发了 p66shc 诱导的细胞凋亡、DNA 损伤反应和 PARP 激活。与单药治疗相比，TS-2021 和奥拉帕利联合使用可协同增加细胞凋亡和 DNA 损伤，并降低 PARP 表达。奥拉帕利促进了 GBM 细胞中 TS-2021 的复制和释放。在机制上，奥拉帕利联合 TS-2021 上调了 p66shc 的磷酸化，增强了肿瘤细胞的凋亡。在体内，联合治疗抑制了肿瘤生长并延长了生存期，证实了协同作用。

结论

本研究首次表明，TS-2021 使具有野生型 BRCA1/2 的 GBM 细胞对奥拉帕利敏感。TS-2021 与奥拉帕利联合使用对 GBM 具有协同治疗作用，为提供了一种有前途的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/30a559da47b7/CNS-30-e70124-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/7f7a0769523d/CNS-30-e70124-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/6d66bf78739f/CNS-30-e70124-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/233efc683cb3/CNS-30-e70124-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/7a04520b0991/CNS-30-e70124-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/c77c157f2357/CNS-30-e70124-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/45631e025d40/CNS-30-e70124-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/30a559da47b7/CNS-30-e70124-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/7f7a0769523d/CNS-30-e70124-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/6d66bf78739f/CNS-30-e70124-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/233efc683cb3/CNS-30-e70124-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/7a04520b0991/CNS-30-e70124-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/c77c157f2357/CNS-30-e70124-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/45631e025d40/CNS-30-e70124-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ca2/11570871/30a559da47b7/CNS-30-e70124-g002.jpg

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J Med Virol. 2024 Jan;96(1):e29335. doi: 10.1002/jmv.29335.
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