Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.

Abstract

The role of angiogenesis in tumor growth and metastasis is well established. Identification of a small molecule that blocks tumor angiogenesis and is safe and affordable has been a challenge in drug development. In this study, we showed that acetyl-11-keto-beta-boswellic acid (AKBA), an active component from an Ayurvedic medicinal plant (Boswellia serrata), could strongly inhibit tumor angiogenesis. AKBA suppressed tumor growth in the human prostate tumor xenograft mice treated daily (10 mg/kg AKBA) after solid tumors reached approximately 100 mm(3) (n = 5). The inhibitory effect of AKBA on tumor growth was well correlated with suppression of angiogenesis. When examined for the molecular mechanism, we found that AKBA significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively suppressed vascular endothelial growth factor (VEGF)-induced microvessel sprouting in rat aortic ring assay ex vivo. Furthermore, AKBA inhibited VEGF-induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells in a dose-dependent manner. Western blot analysis and in vitro kinase assay revealed that AKBA suppressed VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) kinase (KDR/Flk-1) with IC(50) of 1.68 micromol/L. Specifically, AKBA suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, extracellular signal-related kinase, AKT, mammalian target of rapamycin, and ribosomal protein S6 kinase. Our findings suggest that AKBA potently inhibits human prostate tumor growth through inhibition of angiogenesis induced by VEGFR2 signaling pathways.

• Authors: Xiufeng Pang, Zhengfang Yi, Xiaoli Zhang, Bokyung Sung, Weijing Qu, Xiaoyuan Lian, Bharat B Aggarwal, Mingyao Liu
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 14 Pg. 5893-900 (Jul 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19567671 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 11-keto-boswellic acid
• Angiogenesis Inhibitors
• Triterpenes
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Humans
• In Vitro Techniques
• Male
• Medicine, Ayurvedic
• Mice
• Mice, Inbred BALB C
• Neovascularization, Pathologic (metabolism, pathology, prevention & control)
• Neovascularization, Physiologic (drug effects)
• Prostatic Neoplasms (blood supply, pathology, prevention & control)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Triterpenes (pharmacology)
• Vascular Endothelial Growth Factor A (pharmacology)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, metabolism)