(-)-Gossypol suppresses the growth of human prostate cancer xenografts via modulating VEGF signaling-mediated angiogenesis | Academic Article individual record
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 w as 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 mmol/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. ©2011 AACR.

authors
author list (cited authors)
Pang, X., Wu, Y., Wu, Y., Lu, B., Chen, J., Wang, J., ... Liu, M.
publication date
2011
published in
keywords
  • Rats, Sprague-Dawley
  • Xenograft Model Antitumor Assays
  • Prostatic Neoplasms
  • Vascular Endothelial Growth Factor Receptor-2
  • Bcl-X Protein
  • Gossypol
  • Humans
  • Cell Differentiation
  • Rats
  • Endothelial Cells
  • Male
  • Mice, Nude
  • Mice
  • Proto-Oncogene Proteins C-bcl-2
  • Mice, Inbred BALB C
  • Signal Transduction
  • Apoptosis
  • Cell Survival
  • Cell Movement
  • Cell Line
  • Animals
  • Cell Proliferation
  • Aorta
  • Vascular Endothelial Growth Factors
  • Neovascularization, Pathologic
citation count

36