Abstract
In the course of searching for angiogenesis inhibitors from microorganisms, two cyclic peptides, PF1171A (1) and PF1171C (2) were isolated from the soil fungus Penicillium sp. FN070315. In the present study, we investigated the antiangiogenic efficacy and associated mechanisms of 1 and 2 in vitro using human umbilical vein endothelial cells (HUVECs). Compounds 1 and 2 inhibited the proliferation of HUVECs at concentrations not exhibiting cytotoxicity. Moreover, 1 and 2 significantly suppressed vascular endothelial growth factor (VEGF)-induced migration, invasion, proliferation and tube formation of HUVECs as well as neovascularization of the chorioallantoic membrane in developing chick embryos. We also identified an association between the antiangiogenic activity of 1 and 2 and the downregulation of both the phosphorylation of VEGF receptor 2 and the expression of hypoxia inducible factor-1α at the protein level. Taken together, these results further suggest that compounds 1 and 2 will be promising angiogenesis inhibitors.
Highlights
Natural products from microorganisms have provided various chemical templates for clinically useful lead compounds in the pharmaceutical industry [1, 2]
These two known compounds were identified as PF1171A (1) [18, 19] and PF1171C (2) [19, 20] by comparing their physicochemical and spectroscopic data ([α]D, 1H and 13C NMR, HR-ESIMS) with the values reported in the literature (Supporting Information)
To elucidate the possible mechanisms of angiogenesis inhibition by 1 and 2, we investigated their effects on the phosphorylation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) in the human umbilical vein endothelial cells (HUVECs)
Summary
Natural products from microorganisms have provided various chemical templates for clinically useful lead compounds in the pharmaceutical industry [1, 2]. Fungi continue to be a rich source of biologically active secondary metabolites belonging to highly diverse structural classes, including alkaloids, macrolides, terpenoids, and peptides.. Fungi continue to be a rich source of biologically active secondary metabolites belonging to highly diverse structural classes, including alkaloids, macrolides, terpenoids, and peptides.3–6 These fungal metabolites have been reported to possess various biological properties such as antibacterial, antitumor and anti-inflammatory activities [3,4,5,6]. Angiogenesis, the growth of new blood vessels, is a complex process involving several steps including proliferation, migration and formation of capillary tubes in endothelial cells [7, 8]. VEGF has been shown to strongly induce cell migration, proliferation, and tube formation with a unique specificity for endothelial cells
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