Andrographolide inhibits tumor angiogenesis via blocking VEGFA/VEGFR2-MAPKs signaling cascade

Kaikai Shen; Lili Ji; Bin Lu; Chong Xu; Chenyuan Gong; Grant Morahan; Zhengtao Wang

doi:10.1016/j.cbi.2014.04.020

Andrographolide inhibits tumor angiogenesis via blocking VEGFA/VEGFR2-MAPKs signaling cascade

Chem Biol Interact. 2014 Jul 25:218:99-106. doi: 10.1016/j.cbi.2014.04.020. Epub 2014 May 9.

Authors

Kaikai Shen¹, Lili Ji², Bin Lu¹, Chong Xu¹, Chenyuan Gong¹, Grant Morahan³, Zhengtao Wang⁴

Affiliations

¹ The MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
² The MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: lichenyue1307@126.com.
³ Western Australian Institute for Medical Research, The University of Western Australia, Perth, Australia.
⁴ The MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: ztwang@shutcm.edu.cn.

PMID: 24814888
DOI: 10.1016/j.cbi.2014.04.020

Abstract

Traditional medicinal herb Andrographis paniculata is known to possess anti-tumor activity, and its potential active compound is the diterpenoid lactone andrographolide (ANGL). In this study, we have found that ANGL inhibits tumor growth in nude mice bearing xenografted Hep3B cancer cells, concomitant with a reduction in tumor vessel counts. ANGL inhibits vascular endothelial growth factor A (VEGFA)-induced angiogenic responses in vitro and neoangiogenesis in vivo. We also found that ANGL inhibits VEGFA-induced phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream targets such as the mitogen-activated protein kinases (MAPKs). ANGL interferes with the binding of VEGFA to VEGFR2, but has no effect on VEGFR2 kinase activity in vitro. Taken together, our results indicate that ANGL possesses anti-angiogenic activity which is mediated by preventing VEGFA-induced phosphorylation and activation of VEGFR2 and MAPKs. The present study indicates that ANGL can block tumor angiogenesis and therefore represents therapeutic potential for cancer treatment.

Keywords: Andrographolide; Mitogen-activated protein kinases; Tumor angiogenesis; Vascular endothelial growth factor A; Vascular endothelial growth factor receptor 2.

Publication types

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

MeSH terms

Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / pharmacology*
Angiogenesis Inhibitors / therapeutic use
Animals
Cell Survival / drug effects
Cells, Cultured
Diterpenes / chemistry
Diterpenes / pharmacology*
Diterpenes / therapeutic use
Human Umbilical Vein Endothelial Cells
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Nude
Mitogen-Activated Protein Kinases / antagonists & inhibitors*
Mitogen-Activated Protein Kinases / metabolism
Models, Animal
Molecular Structure
Neovascularization, Pathologic / drug therapy
Protein Binding / drug effects
Signal Transduction / drug effects*
Vascular Endothelial Growth Factor A / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Angiogenesis Inhibitors
Diterpenes
Vascular Endothelial Growth Factor A
andrographolide
Vascular Endothelial Growth Factor Receptor-2
Mitogen-Activated Protein Kinases