目的:土贝莫苷-1(TBMS1)是一种具有药理特性和抗肿瘤作用的植物来源的三萜皂苷,但TBMS1的抗肿瘤微血管作用仍有待完全阐明。本研讨旨在验证TBMS1对肿瘤微血管的感化及其根本机制。方法:构建SKOV3异种移植小鼠模型,评价TBMS1的体内抗肿瘤微血管,随后通过功能测定验证TBMS1对增殖的影响,细胞周期,迁移,血管内皮细胞的小管形成。接下来,基于网络药理学,药物/疾病-靶蛋白-蛋白相互作用(PPI)网络,进行生物学功能和基因富集分析以预测潜在的机制。最后,确定了与肿瘤跨内皮迁移相关的分子和途径.结果:TBMS1治疗可有效降低卵巢癌模型中肿瘤微血管密度,抑制细胞增殖,细胞周期,迁移,体外诱导血管内皮细胞凋亡。网络药理学数据表明,肿瘤细胞粘附和跨内皮迁移可能参与了TBMS1的抗血管生成作用。通过内皮粘附和通透性测定,我们发现TBMS1降低了肿瘤的粘附性和内皮单层的通透性。此外,粘附蛋白(VCAM-1和ICAM-1)和紧密连接(TJ)蛋白(VE-cadhsion,发现ZO-1和claudin-5)受到调控。最后,Akt,通过TBMS1处理,Erk1/2、Stat3和NF-κB信号传导降低。结论:综上所述,我们的研究结果强烈提示,TBSM1的临床应用可作为抑制肿瘤进展的血管活性药物治疗.
Objective: Tubeimoside-1 (TBMS1) is a plant-derived triterpenoid saponin that exhibits pharmacological properties and anti-tumor effects, but the anti-tumor microvessels of action of TBMS1 remains to be completely elucidated. This study aims to verify the effect of TBMS1 on tumor microvessels and its underlying mechanism. Methods: A SKOV3 xenografted mouse model were constructed to evaluate the anti-tumor microvessels of TBMS1 in vivo, followed by function assays to verify the effects of TBMS1 on the proliferation, cell cycle, migration, and tubule formation of vascular endothelial cells in vitro. Next, based on network pharmacology, the drug/disease-target protein-protein interaction (PPI) networks, biological functions and gene enrichment analyses were performed to predict the underlying mechanism. Finally, molecules and pathways associated with tumor trans-endothelial migration were identified. Results: TBMS1 treatment effectively reduced tumor microvessel density in ovarian cancer model and inhibited the proliferation, cell cycle, migration, and induced apoptosis of vascular endothelial cells in vitro. Network pharmacological data suggested that tumor cell adhesion and trans-endothelial migration may participate in antiangiogenic effects of TBMS1. By endothelial adhesion and permeability assay, we identified that tumor adhesion and the permeability of endothelial monolayers were reduced by TBMS1. Furthermore, adhesion protein (VCAM-1and ICAM-1) and tight junction (TJ) proteins (VE-cadhsion, ZO-1 and claudin-5) were found to be regulated. Finally, Akt, Erk1/2, Stat3 and NF-κB signaling were decreased by TBMS1 treatment. Conclusion: To sum up, our findings strongly suggest that clinical application of TBSM1 may serve as a vasoactive drug treatment to suppress tumor progression.