(-)-
Gossypol, a natural BH3-mimetic and small-molecule Bcl-2 inhibitor, shows promise in ongoing phase II clinical trials for human
cancers. However, whether (-)-
gossypol plays functional roles in
tumor angiogenesis has not been directly elucidated yet. In this study, we showed that (-)-
gossypol dose dependently inhibited the expression of
VEGF, Bcl-2, and Bcl-xL in human
prostate cancer cells (PC-3 and DU 145) and primary cultured human umbilical vascular endothelial cells (HUVEC) in vitro. Notably, the growth of human prostate
tumor PC-3 xenografts in mice was significantly suppressed by (-)-
gossypol at a dosage of 15 mg/kg/d. This inhibitory action of (-)-
gossypol in vivo was largely dependent on suppression of angiogenesis in the solid
tumors, where
VEGF expression and microvessel density were remarkably decreased. Furthermore, (-)-
gossypol inhibited
VEGF-induced chemotactic motility and tubulogenesis in HUVECs and human microvascular endothelial cells and suppressed microvessel sprouting from rat aortic rings ex vivo. When examined for the mechanism, we found that (-)-
gossypol blocked the activation of
VEGF receptor 2
kinase with the half maximal inhibitory concentration of 2.38 μmol/L in endothelial cells. Consequently, the phosphorylation of key intracellular proangiogenic
kinases induced by
VEGF was all suppressed by the treatment, such as
Src family kinase,
focal adhesion kinase, extracellular signal-related
kinase, and AKT
kinase. Taken together, the present study shows that (-)-
gossypol potently inhibits human prostate
tumor growth through modulating
VEGF signaling pathway, which further validates its great potential in clinical practice.