Abstract
While significant progress has been made in understanding the anti-inflammatory and anti-proliferative effects of the natural diterpenoid component Oridonin on tumor cells, little is known about its effect on tumor angiogenesis or metastasis and on the underlying molecular mechanisms. In this study, Oridonin significantly suppressed human umbilical vascular endothelial cells (HUVECs) proliferation, migration, and apillary-like structure formation in vitro. Using aortic ring assay and mouse corneal angiogenesis model, we found that Oridonin inhibited angiogenesis ex vivo and in vivo. In our animal experiments, Oridonin impeded tumor growth and metastasis. Immunohistochemistry analysis further revealed that the expression of CD31 and vWF protein in xenografts was remarkably decreased by the Oridonin. Furthermore, Oridonin reinforced endothelial cell-cell junction and impaired breast cancer cell transendothelial migration. Mechanistically, Oridonin not only down-regulated Jagged2 expression and Notch1 activity but also decreased the expression of their target genes. In conclusion, our results demonstrated an original role of Oridonin in inhibiting tumor angiogenesis and propose a mechanism. This study also provides new evidence supporting the central role of Notch in tumor angiogenesis and suggests that Oridonin could be a potential drug candidate for angiogenesis related diseases.
Highlights
Tumor neoangiogenesis supplies nutrients and oxygen to enhance tumor growth and, especially, provides the principal route of tumor metastasis which is the main cause of morbidity and mortality in most cancers [1]
Cancer cells escape from the primary tumor, enter into lymphatic or blood circulation, and cross the vessel endothelial cell layer to enter the parenchyma of the target organ
Result showed that Oridonin significantly inhibits vascular endothelial growth factor (VEGF) induced human umbilical vascular endothelial cells (HUVECs) proliferation in a dose-dependent manner, with the IC50 at about 2.5 mM (Fig. 1A right panel)
Summary
Tumor neoangiogenesis supplies nutrients and oxygen to enhance tumor growth and, especially, provides the principal route of tumor metastasis which is the main cause of morbidity and mortality in most cancers [1]. Cancer cells escape from the primary tumor, enter into lymphatic or blood circulation (intravasation), and cross the vessel endothelial cell layer to enter the parenchyma of the target organ. Transendothelial migration (TEM) is a critical step in the metastatic dissemination of malignant cells from a primary tumor to distant vital organs [3]. Inhibition of TEM may be an effective strategy of suppressing tumor growth and metastasis. Among the complex signaling pathways regulating endothelial cell-cell contacts, which determine the permissibility of TEM, the Notch signaling pathway is critical [4]. Upon Notch ligand binding to a receptor on an adjacent cell, the intracellular portion of the receptor is cleaved and translocates into the nucleus, leading to the expression of downstream genes such as Hes-1 and HESR1
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