Abstract
BackgroundWe previously reported the anti-angiogenic activity of paeonol isolated from Moutan Cortex. In the present study, we investigated the negative effect of paeonol oxime (PO, a paeonol derivative) on basic fibroblast growth factor (bFGF)-mediated angiogenesis in human umbilical vein endothelial cells (HUVECs) (including tumor angiogenesis) and pro-survival activity in HT-1080 fibrosarcoma cell line.Methodology/Principal FindingsWe showed that PO (IC50 = 17.3 µg/ml) significantly inhibited bFGF-induced cell proliferation, which was achieved with higher concentrations of paeonol (IC50 over 200 µg). The treatment with PO blocked bFGF-stimulated migration and in vitro capillary differentiation (tube formation) in a dose-dependent manner. Furthermore, PO was able to disrupt neovascularization in vivo. Interestingly, PO (25 µg/ml) decreased the cell viability of HT-1080 fibrosarcoma cells but not that of HUVECs. The treatment with PO at 12.5 µg/ml reduced the levels of phosphorylated AKT and VEGF expression (intracellular and extracelluar) in HT-1080 cells. Consistently, immunefluorescence imaging analysis revealed that PO treatment attenuated AKT phosphorylation in HT-1080 cells.Conclusions/SignificanceTaken together, these results suggest that PO inhibits bFGF-induced angiogenesis in HUVECs and decreased the levels of PI3K, phospho-AKT and VEGF in HT-1080 cells.
Highlights
Angiogenesis in embryonic development, reproduction and wound healing is tightly regulated by the balance between the angiogenic inhibitors and activators [1,2,3,4]
Conclusions/Significance: Taken together, these results suggest that PO inhibits basic fibroblast growth factor (bFGF)-induced angiogenesis in human umbilical vein endothelial cells (HUVECs) and decreased the levels of phosphoinositide 3-kinase (PI3K), phospho-AKT and vascular endothelial growth factor (VEGF) in HT-1080 cells
While VEGF is a primary mediator of angiogenic responses, bFGF is one of potent angiogenesis inducers to stimulate the vascular endothelial mitogenesis and is often involved in pathologic angiogenesis. bFGF is routinely employed as angiogenic polypeptide for experimental studies [9]
Summary
Angiogenesis in embryonic development, reproduction and wound healing is tightly regulated by the balance between the angiogenic inhibitors and activators [1,2,3,4]. While VEGF is a primary mediator of angiogenic responses, bFGF is one of potent angiogenesis inducers to stimulate the vascular endothelial mitogenesis and is often involved in pathologic angiogenesis. The endothelial responses include angiogenic factor-stimulated changes in the vascular endothelial permeability, degradation of the basement membrane by metalloproteases, migration, remodeling and proliferation of endothelial cells to form capillary tubes, and other processes. Interruptions of one or more steps in these processes can negatively affect angiogenesis and inhibit early malignant lesions to lower the cancer risk [10] VEGF expression is mediated by the phosphoinositide 3-kinase (PI3K) pathway in endothelial cells [11]. We investigated the negative effect of paeonol oxime (PO, a paeonol derivative) on basic fibroblast growth factor (bFGF)-mediated angiogenesis in human umbilical vein endothelial cells (HUVECs) (including tumor angiogenesis) and prosurvival activity in HT-1080 fibrosarcoma cell line
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