Saikosaponin b2 inhibits tumor angiogenesis in liver cancer via down-regulation of VEGF/ERK/HIF-1α signaling

Saikosaponin b2 (SSb2) is an active component of Radix Bupleuri, which is commonly used in traditional Chinese medicine for defervescence and liver protection. In the present study, it was demonstrated that SSb2 exhibited potent antitumor activity by inhibiting tumor angiogenesis in vivo and in vitro. As measured by tumor weight and measures of immune function such as thymus index, spleen index and white blood cell count, SSb2 inhibited tumor growth, with low immunotoxicity, in H22 tumor-bearing mice. Furthermore, proliferation and migration of HepG2 liver cancer cells was inhibited following SSb2 treatment, which demonstrated SSb2 ' s antitumor effect. The angiogenesis marker CD34 was downregulated in the SSb2-treated tumor samples, which suggested the antiangiogenic activity of SSb2. Furthermore, the chick chorioallantoic membrane assay demonstrated the potent inhibitory effect of SSb2 on basic fibroblast growth factor-induced angiogenesis. In vitro, SSb2 significantly inhibited numerous stages of angiogenesis, including the proliferation, migration and invasion of human umbilical vein endothelial cells. Further mechanistic studies demonstrated that SSb2 treatment reduced the levels of key proteins involved in angiogenesis, including vascular endothelial growth factor (VEGF), phosphorylated ERK1/2, hypoxia-inducible factor (HIF)-1 alpha, MMP2 and MMP9 in H22 tumor-bearing mice, which supported the HepG2 liver cancer cell results. Overall, SSb2 effectively inhibited angiogenesis via the VEGF/ERK/HIF-1 alpha signal pathway and may serve as a promising natural agent for liver cancer treatment.