Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets...Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets in antiangiogenic drug development. Among them, vascular endothelial growth factor receptor 2 （VEGFR2） inhibitors exerts potent antiangiogenic activity in tumor therapy. Therefore, it may provide a valid strategy for cancer treatment through targeting the tumor angiogenesis via VEGFR2 pathway. In this study, we established a high-profile compounds library and certificated a novel compound named N-（N-pyrrolidylacetyl）-9-（4-bromobenzyl）-l,3,4,9-tetrahydro-^-carboline （YF-452）, which remarkably inhibited the migration, invasion and tube-like structure formation of human umbilical vein endothelial cells （HUVECs） with little toxicity invitro. Rat thoracic aorta ring assay indicated that YF-452 significantly blocked the formation ofmicrovascular exvivo. In addition, YF-452 inhibited angiogenesis in chick chorioallantoic membrane （CAM） and mouse corneal micropocket assays. Moreover, YF-452 remarkably suppressed tumor growth in xenografts mice model. Furthermore, investigation of molecular mechanism revealed that YF-452 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal regulated kinase （ERK）, focal adhesion kinase （FAK） and Src. These results indicate that YF-452 inhibits angiogenesis and may be a potential antiangiogenic drug candidate for cancer therapy.展开更多
基金supported by Major State Basic Research Development Program of China(2015CB910400)National Natural Science Foundation of China(81272463,81472788,81330049,81673304)The Science and Technology Commission of Shanghai Municipality(15431902200)
文摘Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets in antiangiogenic drug development. Among them, vascular endothelial growth factor receptor 2 （VEGFR2） inhibitors exerts potent antiangiogenic activity in tumor therapy. Therefore, it may provide a valid strategy for cancer treatment through targeting the tumor angiogenesis via VEGFR2 pathway. In this study, we established a high-profile compounds library and certificated a novel compound named N-（N-pyrrolidylacetyl）-9-（4-bromobenzyl）-l,3,4,9-tetrahydro-^-carboline （YF-452）, which remarkably inhibited the migration, invasion and tube-like structure formation of human umbilical vein endothelial cells （HUVECs） with little toxicity invitro. Rat thoracic aorta ring assay indicated that YF-452 significantly blocked the formation ofmicrovascular exvivo. In addition, YF-452 inhibited angiogenesis in chick chorioallantoic membrane （CAM） and mouse corneal micropocket assays. Moreover, YF-452 remarkably suppressed tumor growth in xenografts mice model. Furthermore, investigation of molecular mechanism revealed that YF-452 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal regulated kinase （ERK）, focal adhesion kinase （FAK） and Src. These results indicate that YF-452 inhibits angiogenesis and may be a potential antiangiogenic drug candidate for cancer therapy.
