Paeonol exerts anti-angiogenic and anti-metastatic activities through downmodulation of Akt activation and inactivation of matrix metalloproteinases

Paeonol (2′-hydroxy-4′-methoxyacetophenone) is known to possess anti-inflammatory and anti-proliferative activities. Recently there is evidence that anti-inflammatory agents may be useful in the setting of angiogenesisrelated diseases. Thus in the present study the anti-angiogenic activity of paeonol and its mechanism were investigated in vitro and in vivo. Paeonol significantly inhibited proliferation of basic fibroblast growth factor (bFGF)-stimulated human umbilical vein endothelial cells (HUVECs). Paeonol also significantly inhibited migration and tube formation of bFGF-stimulated HUVECs in vitro. In addition, paeonol significantly suppressed neovessel formation on bFGF-treated chick chorioallantoic membrane (CAM) and disrupted bFGF-induced neovascularization in Matrigel plug assay in vivo. Furthermore, paeonol downregluated Akt phosphorylation in bFGF-stimulated HUVECs and reduced expression of matrix metalloproteinases-2 and -9 in HT1080 human fibrosarcoma cells. The Akt inhibitor LY294002 synergistically potentiated paeonol-induced inactivation of Akt and vascular endothelial growth factor in bFGF-treated HUVECs. Taken together, these findings suggest that paeonol can be a potent suppressor of angiogenesis and metastasis partially through inhibition of Akt signaling pathway and matrix metalloproteinase activity.