Steppogenin suppresses tumor growth and sprouting angiogenesis through inhibition of HIF-1α in tumors and DLL4 activity in the endothelium,Phytomedicine

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Steppogenin suppresses tumor growth and sprouting angiogenesis through inhibition of HIF-1α in tumors and DLL4 activity in the endothelium
Phytomedicine ( IF 6.7 ) Pub Date : 2022-10-27 , DOI: 10.1016/j.phymed.2022.154513
Sora Cha ₁ , Hyoung-Geun Kim ₂ , Hyeonha Jang ₁ , Jihoon Lee ₁ , Tang Chao ₁ , Nam-In Baek ₂ , Im-Sook Song ₁ , You Mie Lee ₁

Affiliation

Background

Hypoxia is a characteristic feature of many solid tumors. As an adaptive response to hypoxia, tumor cells activate hypoxia-inducible factor-1α (HIF-1α). Under hypoxic conditions, angiogenesis mediated by HIF-1α is involved in the growth and metastasis of tumor cells. During the angiogenic process, differentiated tip endothelial cells (ECs) characterized by high expression of DLL4 promote angiogenic germination through filopodia. Inhibitors of HIF-1α or DLL4 have been widely studied

Purpose

We tried to find inhibitors targeting both HIF-1α and DLL4 in tumor which have not yet been developed.

Study design

In this study, we examined a natural compound that inhibits sprouting angiogenesis and tumor growth by targeting both HIF-1α and DLL4 under hypoxic conditions.

Methods

After examining cell viability of 70 selected natural compounds, we assessed the effects of compounds on HIF-1α and DLL4 transcriptional activity using a dual-luciferase reporter assay. Western blot analysis, immunofluoresecnt assay and real-time qPCR were performed to identify expression of proteins, such as HIF-1α and DLL4, as well as HIF-1α target genes under hypoxic conditions. In vitro angiogenesis assay and in vivo allograft tumor experiment were performed to investigate inhibition of tumor growth through anti-angiogenic activity.

Results

Among these compounds, steppogenin, which is extracted from the root bark of Morus alba l, respectively inhibited the transcriptional activity of HIF-1α under hypoxic conditions in HEK293T cells and vascular endothelial growth factor (VEGF)-induced DLL4 expression in vascular ECs in a dose-dependent manner. In tumor cells and retinal pigment epithelial cells, steppogenin significantly suppressed HIF-1α protein levels under hypoxic conditions as well as VEGF-induced DLL4 expression in ECs. Furthermore, steppogenin suppressed hypoxia-induced vascular EC proliferation and migration as well as VEGF-induced sprouting of EC spheroids.

Conclusion

These results suggest that the natural compound steppogenin could potentially be used to treat angiogenic diseases, such as those involving solid tumors, because of its dual inhibition of HIF-1α and DLL4.

中文翻译：

Steppogenin 通过抑制肿瘤中的 HIF-1α 和内皮细胞中的 DLL4 活性来抑制肿瘤生长和萌芽血管生成

背景

缺氧是许多实体瘤的特征。作为对缺氧的适应性反应，肿瘤细胞激活缺氧诱导因子 1α (HIF-1α)。缺氧条件下，HIF-1α介导的血管生成参与肿瘤细胞的生长和转移。在血管生成过程中，以 DLL4 高表达为特征的分化尖端内皮细胞 (EC) 通过丝状伪足促进血管生成萌发。HIF-1α 或 DLL4 抑制剂已被广泛研究

目的

我们试图寻找针对肿瘤中HIF-1α和DLL4的抑制剂，但尚未开发出来。

学习规划

在这项研究中，我们研究了一种天然化合物，它在缺氧条件下通过靶向 HIF-1α 和 DLL4 来抑制萌芽血管生成和肿瘤生长。

方法

在检查了 70 种选定的天然化合物的细胞活力后，我们使用双荧光素酶报告基因测定评估了化合物对 HIF-1α 和 DLL4 转录活性的影响。通过Western blot分析、免疫荧光分析和实时qPCR来鉴定低氧条件下HIF-1α和DLL4等蛋白质以及HIF-1α靶基因的表达。进行体外血管生成测定和体内同种异体移植肿瘤实验，以研究通过抗血管生成活性抑制肿瘤生长。

结果

其中，从桑树根皮中提取的steppogenin分别抑制HEK293T细胞缺氧条件下HIF-1α的转录活性和血管内皮生长因子（VEGF）诱导的血管内皮细胞中DLL4的表达。剂量依赖性方式。在肿瘤细胞和视网膜色素上皮细胞中，steppogenin 显着抑制缺氧条件下的 HIF-1α 蛋白水平以及 VEGF 诱导的 EC 中 DLL4 的表达。此外，steppogenin 抑制缺氧诱导的血管 EC 增殖和迁移以及 VEGF 诱导的 EC 球体萌芽。