Abstract
BackgroundGleditsia sinensis thorns have been widely used in traditional Korean medicine for the treatment of several diseases, including obesity, thrombosis, and tumor-related diseases. The aim of the study is to determine the antiangiogenic effect of Gleditsia sinensis thorns in vitro and in vivo in a bid to evaluate its potential as an anticancer drug.MethodsEthanol extract of Gleditsia sinensis thorns (EEGS) were prepared and used for in vitro and in vivo assays. In vitro antiangiogenic effect of EEGS was determined in HUVEC primary cells by cell migration and tube formation assays. In vivo antiangiogenic effect of EEGS was determined by measuring vessel formation and vascular endothelial cells migrating into the implanted matrigels in nude mice. The angiogenesis-related proteins of which expression levels were altered by EEGS were identified by proteomic analysis.ResultsEEGS exerted a dose-dependent antiproliferative effect on HUVEC cells without significant cytotoxicity. Angiogenic properties, such as cell migration and tube formation, were significantly inhibited by EEGS in a dose-dependent manner. New vessel formation was also suppressed by EEGS, as determined by the directed in vivo angiogenesis assays in nude mice. EEGS reduced the expression of proangiogenic proteins, endothelin 1 and matrix metallopeptidase 2, in HUVEC cells.ConclusionsOur findings suggest that EEGS can inhibit angiogenesis by down-regulating proangiogenic proteins, and therefore it should be considered as a potential anticancer drug targeting tumor-derived angiogenesis.
Highlights
Gleditsia sinensis thorns have been widely used in traditional Korean medicine for the treatment of several diseases, including obesity, thrombosis, and tumor-related diseases
Ethanol extract of Gleditsia sinensis thorns (EEGS) inhibits cell proliferation but does not induce cell death in Human umbilical vein endothelial cells (HUVEC) cells Proliferation of endothelial cells in response to angiogenic stimuli is a critical step during new vessel formation [17]
A slight decrease in cell viability was observed in the EEGS-treated HUVEC cells, no significant cytotoxicity was observed at doses of up to 200 μg/mL EEGS during the 48 h cultivation period
Summary
Gleditsia sinensis thorns have been widely used in traditional Korean medicine for the treatment of several diseases, including obesity, thrombosis, and tumor-related diseases. Current antiangiogenic therapies include natural angiogenesis inhibitors (e.g., angiostatin), endothelial cell growth inhibitors (e.g., TNP-470), inhibitors of proangiogenic molecules (e.g., vascular endothelial growth factor [VEGF] receptor antibodies), and therapies that interfere with basement membranes and the extracellular matrix (e.g., tissue inhibitors of matrix metallopeptidases [TIMPs]) [2]. An additional advantage is the ability of antiangiogenic drugs to target newly forming vessels without harming surrounding normal cells; they show lower toxicities than traditional cytotoxic chemotherapeutics. Previous studies have demonstrated that cancer cells release proangiogenic proteins, such as VEGF [7] and basic fibroblast growth factor (FGF2) [4]. These growth factors recruit endothelial cells and promote their proliferation. Small molecules that interfere with the proangiogenic signaling pathway are potential anticancer drugs
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