Isomangiferin, a Novel Potent Vascular Endothelial Growth Factor Receptor 2 Kinase Inhibitor, Suppresses Breast Cancer Growth, Metastasis and Angiogenesis.
- Author:
Banghua WANG
1
;
Jia SHEN
;
Zexia WANG
;
Jianxia LIU
;
Zhifeng NING
;
Meichun HU
Author Information
- Publication Type:Original Article
- Keywords: Angiogenesis inhibitors; Apoptosis; Breast neoplasms; Isomangiferin; Vascular endothelial growth factor receptor-2
- MeSH: Angiogenesis Inhibitors; Animals; Apoptosis; Blood Vessels; Breast Neoplasms; Cell Proliferation; Heterografts; Human Umbilical Vein Endothelial Cells; Humans; In Vitro Techniques; Mice; Microvessels; Neoplasm Metastasis; Phosphotransferases; Rats; Receptors, Vascular Endothelial Growth Factor*; Signal Transduction; Vascular Endothelial Growth Factor A*; Vascular Endothelial Growth Factor Receptor-2*
- From:Journal of Breast Cancer 2018;21(1):11-20
- CountryRepublic of Korea
- Language:English
- Abstract: PURPOSE: Vascular endothelial growth factor (VEGF) signal transduction mainly depends on its binding to VEGF receptor 2 (VEGFR-2). VEGF downstream signaling proteins mediate several of its effects in cancer progression, including those on tumor growth, metastasis, and blood vessel formation. The activation of VEGFR-2 signaling is a hallmark of and is considered a therapeutic target for breast cancer. Here, we report a study of the regulation of the VEGFR-2 signaling pathway by a small molecule, isomangiferin. METHODS: A human breast cancer xenograft mouse model was used to investigate the efficacy of isomangiferin in vivo. The inhibitory effect of isomangiferin on breast cancer cells and the underlying mechanism were examined in vitro. RESULTS: Isomangiferin suppressed tumor growth in xenografts. In vitro, isomangiferin treatment inhibited cancer cell proliferation, migration, invasion, and adhesion. The effect of isomangiferin on breast cancer growth was well coordinated with its suppression of angiogenesis. A rat aortic ring assay revealed that isomangiferin significantly inhibited blood vessel formation during VEGF-induced microvessel sprouting. Furthermore, isomangiferin treatment inhibited VEGF-induced proliferation of human umbilical vein endothelial cells and the formation of capillary-like structures. Mechanistically, isomangiferin induced caspase-dependent apoptosis of breast cancer cells. Furthermore, VEGF-induced activation of the VEGFR-2 kinase pathway was down-regulated by isomangiferin. CONCLUSION: Our findings demonstrate that isomangiferin exerts anti-breast cancer effects via the functional inhibition of VEGFR-2. Pharmaceutically targeting VEGFR-2 by isomangiferin could be an effective therapeutic strategy for breast cancer.
