目的:科学家一直在探索抑制血管生成和阻止肿瘤生长的抗血管生成策略。多形性胶质母细胞瘤(GBM)中的血管生成拟态(VM)提出了挑战,复杂的抗血管生成治疗。一种新型药物,GN25(3-[{1,4-二氢-5,8-二甲氧基-1,4-二氧代-2-萘基}硫代]-丙酸),可以抑制肿瘤的形成。本研究旨在探讨GN25在抗血管生成和抗VM中的微环境效应和分子机制。
方法:采用MTT(3-(4,5-二甲基噻唑基-2)-2,5-二苯基四唑溴化物)试验评价不同浓度GN25在人脐静脉内皮细胞(HUVEC)和Uppsala87恶性胶质瘤(U87MG)细胞中的细胞活力。功能分析用于研究GN25对血管生成相关过程的影响。而明胶酶谱,酶联免疫吸附测定,采用免疫印迹法评估其对基质金属蛋白酶(MMP)-2和血管内皮生长因子(VEGF)分泌及相关信号通路的影响。
结果:GN25抑制了迁移,伤口愈合,在大鼠主动脉环和斑马鱼胚胎模型中,HUVECs中的管形成和血管生成中断。GN25剂量依赖性地减少磷脂酰肌醇3-激酶/AKT并抑制HUVECs中MMP-2/VEGF的分泌。在U87MG细胞,GN25抑制迁移,伤口愈合,和VM,伴随着MMP-2和VEGF分泌的减少。结果表明,GN25有效抑制HUVEC和U87MG细胞中的血管生成和VM形成,而不影响预先存在的血管结构。
结论:本研究通过阐明GN25对经典血管生成的抑制作用,阐述了GN25作为抗血管生成剂的潜力。VM为开发针对肿瘤进展和血管生成相关疾病的新型治疗策略提供了有价值的见解。这些结果表明GN25作为血管生成相关疾病的有希望的候选物的潜力。
OBJECTIVE: Scientists have been exploring anti-angiogenic strategies to inhibit angiogenesis and prevent tumor growth. Vasculogenic mimicry (VM) in glioblastoma multiforme (GBM) poses a challenge, complicating anti-angiogenesis therapy. A novel drug, GN25 (3-[{1,4-dihydro-5,8-dimethoxy-1,4-dioxo-2-naphthalenyl}thio]-propanoic acid), can inhibit tumor formation. This study aims to investigate the microenvironmental effects and molecular mechanisms of GN25 in anti-angiogenesis and anti-VM.
METHODS: MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay was used to evaluate the cell viability of different concentrations of GN25 in human umbilical vein endothelial cells (HUVEC) and Uppsala 87 malignant glioma (U87MG) cells. Functional assays were used to investigate the effects of GN25 on angiogenesis-related processes, whereas gelatin zymography, enzyme-linked immunosorbent assays, and Western blotting were utilized to assess the influence on matrix metalloproteinase (MMP)-2 and vascular endothelial growth factor (VEGF) secretion and related signaling pathways.
RESULTS: GN25 suppressed migration, wound healing, and tube formation in HUVECs and disrupted angiogenesis in a rat aorta ring and zebrafish embryo model. GN25 dose-dependently reduced phosphatidylinositol 3-kinase/AKT and inhibited MMP-2/VEGF secretion in HUVECs. In U87MG cells, GN25 inhibited migration, wound healing, and VM, accompanied by a decrease in MMP-2 and VEGF secretion. The results indicate that GN25 effectively inhibits angiogenesis and VM formation in HUVECs and U87MG cells without affecting preexisting vascular structures.
CONCLUSIONS: This study elaborated GN25\'s potential as an anti-angiogenic agent by elucidating its inhibitory effects on classical angiogenesis. VM provides valuable insights for developing novel therapeutic strategies against tumor progression and angiogenesis-related diseases. These results indicate the potential of GN25 as a promising candidate for angiogenesis-related diseases.