Eupafolin Exhibits Potent Anti-Angiogenic and Antitumor Activity in Hepatocellular Carcinoma

Abstract

Eupafolin is a flavonoid extracted from the common sage herb which has been used in China as traditional medicine. Previous studies had reported that eupafolin had antioxidative, anti-inflammatory and antitumor effects. However, the function and the mechanism of eupafolin to exert its antitumor activity, especially its effect on tumor angiogenesis, have not been elucidated. Herein, we showed that eupafolin significantly inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation, migration and tube formation of human umbilical vascular endothelial cells (HUVECs) in a dose-dependent manner. Meanwhile, the new blood microvessels induced by VEGF in the matrigel plug were also substantially suppressed by eupafolin. The results of HCC xenograft experiments demonstrated eupafolin remarkably inhibited tumor growth and tumor angiogenesis in vivo, suggesting the antitumor activity exerted by eupafolin was closely correlated with its potency on tumor angiogenesis. Mechanism investigations revealed that eupafolin significantly blocked VEGF-induced activation of VEGFR2 in HUVEC cells as well as its downstream signaling pathway. In addition to the effect on endothelial cells, through inhibiting Akt activity in tumor cells, VEGF secretion in HepG2 was dramatically decreased after eupafolin treatment. Our study was the first to report the activity of eupafolin against tumor angiogenesis as well as the underlying mechanism by which eupafolin to exert its anti-angiogenic activity.

Eupafolin alleviates cerebral ischemia/reperfusion injury in rats via blocking the TLR4/NF‑κB signaling pathway

“…Published reports have mainly focused on in vitro studies, and are lacking evidence from in vivo studies for clinical therapy (30). Jiang et al (14) demonstrated that eupafolin at 60 mg/kg significantly inhibited tumor growth and tumor angiogenesis in a hepatocellular carcinoma xenograft model. The present study investigated the protective effects of eupafolin on cerebral I/R injury in rats and revealed that eupafolin at a dose of 10, 20 and 50 mg/kg all exhibited significant protective effects on cerebral I/R via inhibiting inflammation, oxidative stress and apoptosis.…”

“…Eupafolin alleviates cerebral ischemia/reperfusion injury in rats via blocking the TLR4/NF-κB signaling pathway activation and also resulted in nuclear translocation (12). In addition, the suppressive effects of eupafolin on various tumor types, including esophageal cancer, hepatocellular carcinoma, renal carcinoma and prostate cancer has been extensively studied (13)(14)(15)(16). These data suggested the potential value of eupafolin in treating cancer and inflammation-related diseases.…”

The Potential and Action Mechanism of Polyphenols in the Treatment of Liver Diseases

“…Flavones including eupafolin and morusin showed significant antiangiogenic abilities by in vitro and in vivo studies. Eupafolin could block vascular endothelial growth factor- (VEGF-) induced activation of vascular endothelial growth factor receptor 2 (VEGFR2) in Akt activity in human umbilical vascular endothelial cells and inhibit Akt activity and VEGF secretion in HepG2 [ 142 ]. The other flavone, morusin, inhibited angiogenesis in HepG2 xenograft mice model via attenuation of the IL-6 and signal transducer and activator of transcription 3 (STAT3) signaling pathway [ 143 ].…”

Flavonoids Distinctly Stabilize Lymph Endothelial- or Blood Endothelial Disintegration Induced by Colon Cancer Spheroids SW620

“…[ 27 ], and a similar activity for nepetin was observed in HEPG2 and HEPG3 xenografts (60 mg/kg, 3x per week, i.p.) [ 28 ]. Specifically, nepetin reduced the migration and tube formation of HUVECs and the neo-angiogenesis in xenograft tumors [ 28 ], and furthermore, nepetin inhibited ICAM-1 expression through nuclear factor-kappa B (NF-kB) in A549 human lung airway epithelial cells [ 29 ].…”

“…[ 28 ]. Specifically, nepetin reduced the migration and tube formation of HUVECs and the neo-angiogenesis in xenograft tumors [ 28 ], and furthermore, nepetin inhibited ICAM-1 expression through nuclear factor-kappa B (NF-kB) in A549 human lung airway epithelial cells [ 29 ]. We have demonstrated that the adhesion of breast cancer cells and LECs, similar to the adhesion of colon cancer cells and LECs [ 30 ], is mandatory for intravasation and depends on ICAM-1 in LECs [ 31 , 32 ].…”