Morelloflavone, a
biflavonoid extracted from Garcinia dulcis, has shown antioxidative,
antiviral, and anti-inflammatory properties. However, the function and the mechanism of this compound in
cancer treatment and
tumor angiogenesis have not been elucidated to date. In this study, we postulated that
morelloflavone might have the ability to inhibit angiogenesis, the pivotal step in
tumor growth, invasiveness, and
metastasis. We showed that
morelloflavone could inhibit
vascular endothelial growth factor (
VEGF)-induced cell proliferation, migration, invasion, and capillary-like tube formation of primary cultured human umbilical vascular endothelial cells in a dose-dependent manner.
Morelloflavone effectively inhibited microvessel sprouting of endothelial cells in the mouse aortic ring assay and the formation of new blood microvessels induced by
VEGF in the mouse
Matrigel plug assay. Furthermore,
morelloflavone inhibited
tumor growth and
tumor angiogenesis of
prostate cancer cells (PC-3) in xenograft mouse
tumor model in vivo, suggesting that
morelloflavone inhibited
tumorigenesis by targeting angiogenesis. To understand the underlying mechanism of
morelloflavone on the inhibitory effect of
tumor growth and angiogenesis, we showed that
morelloflavone could inhibit the activation of both RhoA and Rac1
GTPases but have little effect on the activation of Cdc42
GTPase. Additionally,
morelloflavone inhibited the phosphorylation and activation of Raf/
mitogen-activated protein kinase/
extracellular signal-regulated kinase (ERK)
kinase/ERK pathway
kinases without affecting
VEGF receptor 2 activity. Together, our results indicate that
morelloflavone exerts antiangiogenic action by targeting the activation of
Rho-GTPases and ERK signaling pathways. These findings are the first to reveal the novel functions of
morelloflavone in
tumor angiogenesis and its molecular basis for the anticancer action.