(−)-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 demonstrated that (−)-gossypol dose-dependently inhibited the expression of vascular endothelial growth factor (VEGF), Bcl-2 and Bcl-xL in human prostate cancer cells (PC-3 and DU 145) and human primary cultured umbilical vein endothelial cells (HUVECs) in vitro. Notably, the growth of human prostate tumor PC-3 xenografts in mice was significantly suppressed by (−)-gossypol at 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, VEGF-triggered phosphorylation of key intracellular proangiogenic molecules, such as Src family kinase, focal adhesion kinase, extracellular signal-related kinase and AKT kinase, were all suppressed by the treatment. Taken together, the present study demonstrates that (−)-gossypol potently inhibits human prostate tumor growth through modulating VEGF signaling pathway, which further validates its great potential in clinical practice.

Laminin receptor specific therapeutic gold nanoparticles ( 198 AuNP-EGCg) show efficacy in treating prostate cancer

“…We have used a unilateral flank model of prostate cancer derived from human PC-3 cells in SCID mice model, a promising platform for prostate cancer (37)(38)(39)(40).…”

Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

“…More recently, ongoing investigations have focused on its antitumor activity (Cengiz et al, 2010) as a result of documented antineoplastic activity in human breast adenocarcinoma (Van Poznak et al, 2001;Van Poznak and Seidman, 2002;Pang et al, 2011) and metastatic prostate cancer (Huang et al, 2009). Inhibition of the apoptosis regulatory proteins B-cell lymphoma-extra-large and B-cell lymphoma 2 was thought to underlie gossypol's beneficial effects in cancer treatment (Huang et al, 2010).…”

Regulation of vascular endothelial growth factor in prostate cancer

“…As described earlier in the present review, most xenograft models use primary PCa tissue; however, PCa cell lines have been exploited in a subset of studies. For example, PC3 has been used to investigate the use of drugs to inhibit VEGF signaling (Anai et al 2011, Pang et al 2011a. Similarly, the LNCaP-LN3 orthotopic xenograft has been used to evaluate the response of bone metastasis to the anti-VEGF receptor antibody DC101 (Sweeney et al 2002).…”