Abstract
Anti-angiogenesis targeting vascular endothelial growth factor receptor-2 (VEGFR-2) has been considered as an important strategy for cancer therapy. Penduliflaworosin is a diterpenoid isolated from the plant Croton crassifolius. Our previous study showed that this diterpenoid possesses strong anti-angiogenic activity by inhibiting vessel formation in zebrafish. This study was conducted to further investigate the anti-angiogenic activity and mechanism of penduliflaworosin. Results revealed that penduliflaworosin significantly inhibited VEGF-induced angiogenesis processes including proliferation, invasion, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). Moreover, it notably inhibited VEGF-induced sprout formation of aortic rings and blocked VEGF-induced vessel formation in mice. Western blotting studies showed that penduliflaworosin inhibited phosphorylation of the VEGF receptor-2 and its downstream signaling mediators in HUVECs, suggesting that the anti-angiogenic activity was due to an interference with the VEGF/VEGF receptor-2 pathway. In addition, molecular docking simulation indicated that penduliflaworosin could form hydrogen bonds within the ATP-binding region of the VEGF receptor-2 kinase unit. Finally, cytotoxicity assay showed that penduliflaworosin possessed little toxicity toward both cancer and normal cells. Taken together, our findings demonstrate that penduliflaworosin exerts its anti-angiogenic effect via the VEGF receptor-2 signaling pathway. The anti-angiogenic property and low cytotoxicity of penduliflaworosin suggest that it may be useful in cancer treatments.
Highlights
Angiogenesis is the process by which new blood vessels develop from preexisting vasculature [1].The angiogenic process plays an important role in tumor growth, invasion, and metastasis because this process increases the supply of nutrients, oxygen, and growth factors to solid tumors and facilitates the removal of metabolic waste from tumors [2]
Lactate dehydrogenase (LDH) toxicity assay was carried out to determine whether penduliflaworosin was toxic to the human umbilical vein endothelial cells (HUVECs)
The results showed that penduliflaworosin inhibited the migratory process that penduliflaworosin inhibited the migratory process and tube formation of HUVECs induced by and tube formation of HUVECs induced by VEGF
Summary
Angiogenesis is the process by which new blood vessels develop from preexisting vasculature [1]. The angiogenic process plays an important role in tumor growth, invasion, and metastasis because this process increases the supply of nutrients, oxygen, and growth factors to solid tumors and facilitates the removal of metabolic waste from tumors [2]. Blocking angiogenesis is an approach to arrest tumor growth and metastasis, and targeting angiogenesis has become an attractive therapeutic strategy for cancer treatment [3,4]. Angiogenesis is a complex process regulated by a balance between pro- and anti-angiogenic. Angiogenesis a complex process regulated growth by a balance between and anti-angiogenic factors. Among these is factors, vascular endothelial factor (VEGF)prois the most potent angiogenesis
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