Hovenia dulcis Thunb. and its active compound ampelopsin inhibit angiogenesis through suppression of VEGFR2 signaling and HIF-1α expression

Abstract

Specific inhibition of angiogenesis has been considered a powerful strategy for the treatment of cancer and other angiogenesis-related human diseases. Hovenia dulcis Thunb., Japanese raisin tree or Oriental raisin tree, is a hardy tree found in Asia, Eastern China and Korea and has been known to possess various biological activities, including antifatigue, antidiabetic, neuroprotective and hepatoprotective activity. In the present study, for the first time, we evaluated whether a 100% ethanol extract of Hovenia dulcis Thunb. (HDT) inhibits the angiogenesis of human umbilical vein endothelial cells (HUVECs) using in vitro angiogenesis assays. HDT suppressed vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion and tube formation of HUVECs at subtoxic doses. In addition, HDT significantly inhibited in vivo angiogenesis of the chorioallantoic membrane from growing chick embryos without exhibiting cytotoxicity. Furthermore, HDT downregulated not only VEGF receptor 2 (VEGFR2) signaling in HUVECs, but also hypoxia-inducible factor (HIF)-1α expression in hepatocarcinoma cell line HepG2. Ampelopsin is a bioactive flavanonol found in Hovenia dulcis Thunb. Our data showed that ampelopsin inhibited angiogenesis with no cytotoxicity by suppressing both VEGFR2 signaling and HIF-1α expression. These results suggest that Hovenia dulcis Thunb. and its active compound ampelopsin exhibit potent antiangiogenic activities and therefore could be valuable for the prevention and treatment of angiogenesis-related diseases including cancer.

Hovenia dulcis Thumberg: Phytochemistry, Pharmacology, Toxicology and Regulatory Framework for Its Use in the European Union

“…In HepG2 cells, at the concentration of 100 µg/mL, the extract inhibited the expression of HIF-1α. DHM, one of the main secondary metabolites secreted by H. dulcis, showed the same antiangiogenic activity of the extract, through the inhibition of VEGFR2 signal transduction and suppressing the expression of HIF-1α/VEGF [21]; thus, in this case, the claimed biological activity was linked to a specific compound and not to the whole phytocomplex.…”

“…In another study, it was demonstrated that branches extract did not induce toxicity below 10 µg/mL on HaCat cells [49]. Han et al showed that the viability of human umbilical vein endothelial cells (HUVECs) was not affected when exposed to ethanol H. dulcis branches extract in a concentration range of 0-100 µg/mL for 72 h. A 50% reduction of cell viability was observed at 200 µg/mL [21]. The cytotoxicity of fruits extract of H. dulcis on 3T3-L1 cells was assessed at various concentrations (10-300 µg/mL −1 ).…”

“…In the same year, 1997, a Japanese study described the inhibitory effect of H. dulcis methanol extract on the alcohol-induced muscular relaxation, highlighting DHM as the most bioactive compound [18]. In 2012, Shen et al demonstrated the role of DHM in counteracting alcohol intoxication and dependence and suggested it as a therapeutic candidate in alcohol abuse syndrome [19]; in 2014, Zhou et al [20] reported a study showing how DHM treatment can significantly lower the levels of blood glucose and insulin and in 2017, DHM was found to be responsible for the antiangiogenic activity ascribed to H. dulcis and suggested it as potential drug candidate for preventing angiogenesis-related disease, including cancer [21]. In 2018, Dong et al proposed a mechanism of action concerning the hepatoprotective activity of H. dulcis fruit extract, and a further study of the same authors elucidated the direct involvement of DHM in the metabolism of acetaminophen endowing the use of fruits as an herbal remedy for preventing acetaminophen-induced liver injury [22,23].…”

Regulation of signaling pathways by Ampelopsin (Dihydromyricetin) in different cancers: exploring the highways and byways less travelled

“…Ampelopsin effectively reduced the phosphorylated levels of VEGFR2, AKT and ERK1/2 in HUVECs (Human umbilical vein endothelial cells) (23). Ampelopsin exerted repressive effects on HIF-1α expression and its transcriptional target VEGF in HepG2 cells (23).…”

Target Identification of the Marine Natural Products Dictyoceratin-A and -C as Selective Growth Inhibitors in Cancer Cells Adapted to Hypoxic Environments

“…The marine environment is a rich source of drug leads because of its chemical and biological diversity. Indeed, some compounds, including ampelopsin [3], salternamide A [4], eudistidine A [5], discorhabdins [6], laurenditerpenol [7], and strongylophorines [8], have been found to inhibit HIF-1α or its signaling pathway. To date, we have also screened the extracts of marine organisms to discover bioactive natural products showing selective growth inhibition in hypoxia-adapted DU145 human prostate cancer cells.…”