(-)-Gossypol suppresses the growth of human prostate cancer xenografts via modulating VEGF signaling-mediated angiogenesis.

Abstract

(-)-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.

• Authors: Xiufeng Pang, Yuanyuan Wu, Yougen Wu, Binbin Lu, Jing Chen, Jieqiong Wang, Zhengfang Yi, Weijing Qu, Mingyao Liu
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 5 Pg. 795-805 (May 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21372225 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-bcl-2
• Vascular Endothelial Growth Factors
• bcl-X Protein
• Vascular Endothelial Growth Factor Receptor-2
• Gossypol

Topics

• Animals
• Aorta (drug effects)
• Apoptosis (drug effects)
• Cell Differentiation (drug effects)
• Cell Line
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Endothelial Cells (metabolism)
• Gossypol (chemistry, pharmacology)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neovascularization, Pathologic (physiopathology)
• Prostatic Neoplasms (physiopathology)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)
• Vascular Endothelial Growth Factors (genetics, metabolism)
• Xenograft Model Antitumor Assays
• bcl-X Protein (metabolism)