Combined inhibition of WEE1 by AZD1775 synergistically enhances CX-5461 mediated DNA damage and induces cytotoxicity in glioblastoma

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-08-18 DOI:10.1016/j.tice.2025.103093

Meng Cheng , Rui Wang , Ying Pang , Xu Chen , Jing Zhang , Chunlong Zhong

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引用次数: 0

Abstract

Glioblastoma (GBM) is an extremely aggressive type of central nervous system tumors that poses treatment challenges due to its resistance to DNA-damaging therapies. G-quadruplexes (G4) are non-canonical DNA structures involved in genomic stability and transcription regulation, and they have emerged as potential therapeutic targets. Originally developed as an RNA polymerase I inhibitor, CX-5461 has been demonstrated to enhance G4 stabilization and induce DNA damage; however, its effects on GBM remain underexplored. This study investigated the effects of CX-5461 on GBM cell biological functions. CX-5461 treatment significantly inhibited DNA replication and induced apoptosis in GBM. S-phase arrest in cell cycle analysis indicated replication stress, and DNA damage assays revealed extensive double-strand breaks. CX-5461 disrupted the DNA damage response by stabilizing G4 structures, resulting in sustained DNA damage accumulation. Moreover, the combined administration of CX-5461 and the WEE1 inhibitor AZD1775 synergistically decreased cell proliferation and enhanced cell apoptosis. Consequently, these results suggest that CX-5461 inhibited GBM progression by stabilizing G4, causing replication stress and exacerbating DNA damage. Targeting G4 structures, especially when combined with checkpoint inhibitors, provides a hopeful therapeutic approach to improve the effectiveness of GBM therapy.

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AZD1775联合抑制WEE1可协同增强CX-5461介导的DNA损伤并诱导胶质母细胞瘤细胞毒性

胶质母细胞瘤（GBM）是一种极具侵袭性的中枢神经系统肿瘤，由于其对dna损伤疗法的抵抗，给治疗带来了挑战。g -四联体（G4）是非规范的DNA结构，参与基因组稳定性和转录调控，它们已成为潜在的治疗靶点。CX-5461最初是作为RNA聚合酶I抑制剂开发的，已被证明可以增强G4的稳定性并诱导DNA损伤；然而，其对GBM的影响仍未得到充分探讨。本研究探讨了CX-5461对GBM细胞生物学功能的影响。CX-5461处理显著抑制DNA复制，诱导GBM细胞凋亡。细胞周期分析中的s期阻滞表明复制应激，DNA损伤分析显示广泛的双链断裂。CX-5461通过稳定G4结构破坏DNA损伤反应，导致持续的DNA损伤积累。此外，CX-5461和WEE1抑制剂AZD1775联合给药可协同降低细胞增殖，增强细胞凋亡。因此，这些结果表明，CX-5461通过稳定G4，引起复制应激和加剧DNA损伤来抑制GBM的进展。靶向G4结构，特别是与检查点抑制剂联合使用，为提高GBM治疗的有效性提供了一种有希望的治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.