Rhaponticin decreases the metastatic and angiogenic abilities of cancer cells via suppression of the HIF-1 pathway

Rhaponticin (RA; 35-dihydroxy-4-methoxystilbene 3-O--D-glucopyranoside) is a component isolated from various medicinal herbs including Rheum undulatum L. RA has been reported to be an effective treatment for allergy, diabetes, thrombosis, liver steatosis, lung fibrosis and colitis. In addition, RA effectively inhibits tumor growth and induces apoptosis; however, the effects of RA, at non-cytotoxic doses, on the metastasis and angiogenesis of malignant cancer cells have, to be the best of our knowledge, not been identified. In the present study, it was identified that RA suppressed the metastatic potential of MDA-MB231 breast cancer cells, including colony formation, migration and invasion. Human umbilical vein endothelial cells (HUVECs) treated with RA exhibited a decreased ability to form tube-like networks and to migrate across a Transwell membrane, when compared with RA-untreated HUVECs. Using the chick chorioallantoic membrane assay, RA treatment significantly suppressed spontaneous and vascular endothelial growth factor (VEGF)-induced angiogenesis. Furthermore, RA inhibited the production of pro-angiogenic factors, including matrix metalloproteinase (MMP)-9, pentraxin-3, interleukin-8, VEGF and placental growth factor under normoxic and hypoxic conditions, and suppressed the phorbol 12-myristate 13-acetate-induced increase in the gelatinolytic MMP-9 activity and MMP-9 expression in HT1080 cells. RA also significantly inhibited the hypoxia-inducible factor (HIF)-1 pathway, leading to decreased HIF-1 accumulation and HIF-1 nuclear expression under hypoxia. These results indicated that RA exhibits potent anti-metastatic and anti-angiogenic activities with no cytotoxicity via suppression of the HIF-1 signaling pathway. Thus, RA may control malignant cancer cells by inhibiting the spread from primary tumors and expansion to distant organs.