Oridonin inhibits tumor growth and metastasis through anti-angiogenesis by blocking the Notch signaling

Yanmin Dong; Tao Zhang; Jingjie Li; Huayun Deng; Yajuan Song; Dong Zhai; Yi Peng; Xiaoling Lu; Mingyao Liu; Yongxiang Zhao; Zhengfang Yi

doi:10.1371/journal.pone.0113830

Oridonin inhibits tumor growth and metastasis through anti-angiogenesis by blocking the Notch signaling

PLoS One. 2014 Dec 8;9(12):e113830. doi: 10.1371/journal.pone.0113830. eCollection 2014.

Authors

Affiliations

¹ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
² Biological Targeting Diagnosis and Therapy Research Center, Guangxi Medical University, 22 Shuang Yong Rd, Nanning, Guangxi 530021, China.
³ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas 77030, United States of America.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / pharmacology*
Animals
Antineoplastic Agents / pharmacology*
Calcium-Binding Proteins / metabolism
Cell Communication / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Disease Models, Animal
Diterpenes, Kaurane / pharmacology*
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Intercellular Signaling Peptides and Proteins / metabolism
Male
Membrane Proteins / metabolism
Mice
Neoplasm Metastasis
Neoplasms / drug therapy
Neoplasms / metabolism*
Neoplasms / pathology*
Neovascularization, Pathologic / drug therapy
Neovascularization, Pathologic / metabolism*
Rats
Receptors, Notch / metabolism*
Serrate-Jagged Proteins
Signal Transduction / drug effects*
Tumor Burden / drug effects
Vascular Endothelial Growth Factor A / pharmacology
Xenograft Model Antitumor Assays

Substances

Angiogenesis Inhibitors
Antineoplastic Agents
Calcium-Binding Proteins
Diterpenes, Kaurane
Intercellular Signaling Peptides and Proteins
Membrane Proteins
Receptors, Notch
Serrate-Jagged Proteins
Vascular Endothelial Growth Factor A
oridonin

Grants and funding

This study was partially supported by Major State Basic Research Development Program of China (2015CB910400). National Natural Science Foundation of China (81272463, 81472788, 81330049). Program for Changjiang Scholars and Innovative Research Team in University (IRT1128). Innovation Program of Shanghai Municipal Education Commission (13zz034). The Science and Technology Commission of Shanghai Municipality (11DZ2260300). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.