Rhaponticin (RA; 3'5-dihydroxy-4'-methoxystilbene 3-O-β-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)-1α pathway, leading to decreased HIF‑1α accumulation and HIF‑1α 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‑1α signaling pathway. Thus, RA may control malignant
cancer cells by inhibiting the spread from primary
tumors and expansion to distant organs.