1'-Acetoxychavicol acetate suppresses angiogenesis-mediated human prostate tumor growth by targeting VEGF-mediated Src-FAK-Rho GTPase-signaling pathway.

Abstract

Cancer therapeutic agents that are safe, effective and affordable are urgently needed. We describe that 1'-acetoxychavicol acetate (ACA), a component of Siamese ginger (Languas galanga), can suppress prostate tumor growth by largely abrogating angiogenesis. ACA suppressed vascular endothelial growth factor (VEGF)-induced proliferation, migration, adhesion and tubulogenesis of primary cultured human umbilical vascular endothelial cells (HUVECs) in a dose-dependent manner. ACA also inhibited VEGF-induced microvessel sprouting from aortic rings ex vivo and suppressed new vasculature formation in Matrigel plugs in vivo. We further demonstrated that the mechanisms of this chavicol were to block the activation of VEGF-mediated Src kinase, focal adhesion kinase (FAK) and Rho family of small guanosine triphosphatases (GTPases) (Rac1 and Cdc42 but not RhoA) in HUVECs. Furthermore, treatment of human prostate cancer cells (PC-3) with ACA resulted in decreased cell viability and suppression of angiogenic factor production by interference with dual Src/FAK kinases. After subcutaneous administration to mice bearing human prostate cancer PC-3 xenografts, ACA (6 mg/kg/day) remarkably inhibited tumor volume and tumor weight and decreased levels of Src, CD31, VEGF and Ki-67. As indicated by immunohistochemistry and TUNEL analysis, microvessel density and cell proliferation were also dramatically suppressed in tumors from ACA-treated mice. Taken together, our findings suggest that ACA targets the Src-FAK-Rho GTPase pathway, leading to the suppression of prostate tumor angiogenesis and growth.

• Authors: Xiufeng Pang, Li Zhang, Li Lai, Jing Chen, Yuanyuan Wu, Zhengfang Yi, Jian Zhang, Weijing Qu, Bharat B Aggarwal, Mingyao Liu
• Journal: Carcinogenesis (Carcinogenesis) Vol. 32 Issue 6 Pg. 904-12 (Jun 2011) ISSN: 1460-2180 [Electronic] England
• PMID: 21427164 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Benzyl Alcohols
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• Xanthine Oxidase
• Focal Adhesion Kinase 1
• Ptk2 protein, mouse
• src-Family Kinases
• rho GTP-Binding Proteins
• 1'-acetoxychavicol acetate

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Apoptosis (drug effects)
• Benzyl Alcohols (therapeutic use)
• Blotting, Western
• Cell Adhesion (drug effects)
• Cell Cycle (drug effects)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Endothelium, Vascular (cytology, drug effects, metabolism)
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Humans
• Male
• Mice
• Neovascularization, Pathologic (prevention & control)
• Prostatic Neoplasms (blood supply, drug therapy, metabolism)
• RNA, Messenger (genetics)
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Umbilical Veins (cytology, drug effects, metabolism)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, genetics, metabolism)
• Xanthine Oxidase (antagonists & inhibitors)
• Xenograft Model Antitumor Assays
• rho GTP-Binding Proteins (genetics, metabolism)
• src-Family Kinases (genetics, metabolism)