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

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2024-11-18 DOI:10.1111/cns.70124

Yida Liu, Sheng Fang, Peiwen Wang, Junwen Zhang, Fusheng Liu

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引用次数: 0

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.

Abstract Image

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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肿瘤溶解性腺病毒对胶质母细胞瘤的疗效

目的：多形性胶质母细胞瘤（GBM）患者无法从目前的癌症治疗中获益，其预后令人沮丧。本研究旨在探讨第三代溶瘤腺病毒TS-2021与PARP抑制剂奥拉帕利（olaparib）联合治疗GBM的潜在协同作用：方法：在GBM细胞中评估了TS-2021对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 小鼠模型中考察了 TS-2021 和奥拉帕利的协同作用。机理研究的重点是 p66shc 磷酸化在观察到的效应中的作用：结果：TS-2021可引发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 和奥拉帕利联合用药可协同增加细胞凋亡和 DNA 损伤，减少 PARP 表达。奥拉帕利促进了TS-2021在GBM细胞中的复制和释放。从机理上讲，奥拉帕利与 TS-2021 联用可上调 p66shc 磷酸化，从而增强肿瘤细胞凋亡。在体内，联合疗法抑制了肿瘤生长并延长了生存期，证实了其协同作用：本研究首次表明，TS-2021能使野生型BRCA1/2的GBM细胞对奥拉帕尼敏感。TS-2021和奥拉帕利的联合疗法对GBM具有协同治疗效果，是一种很有前景的治疗策略。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.