z-Guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, inhibits angiogenesis in vitro and in vivo.

Abstract

Our previous studies have shown that z-guggulsterone, a constituent of Indian Ayurvedic medicinal plant Commiphora mukul, inhibits the growth of human prostate cancer cells by causing apoptosis. We now report a novel response to z-guggulsterone involving the inhibition of angiogenesis in vitro and in vivo. The z-guggulsterone treatment inhibited capillary-like tube formation (in vitro neovascularization) by human umbilical vein endothelial cells (HUVEC) and migration by HUVEC and DU145 human prostate cancer cells in a concentration- and time-dependent manner. The z- and E-isomers of guggulsterone seemed equipotent as inhibitors of HUVEC tube formation. The z-guggulsterone-mediated inhibition of angiogenesis in vitro correlated with the suppression of secretion of proangiogenic growth factors [e.g., vascular endothelial growth factor (VEGF) and granulocyte colony-stimulating factor], down-regulation of VEGF receptor 2 (VEGF-R2) protein level, and inactivation of Akt. The z-guggulsterone-mediated suppression of DU145 cell migration was increased by knockdown of VEGF-R2 protein level. Ectopic expression of constitutively active Akt in DU145 cells conferred protection against z-guggulsterone-mediated inhibition of cell migration. Oral gavage of 1 mg z-guggulsterone/d (five times/wk) to male nude mice inhibited in vivo angiogenesis in DU145-Matrigel plug assay as evidenced by a statistically significant decrease in tumor burden, microvessel area (staining for angiogenic markers factor VIII and CD31), and VEGF-R2 protein expression. In conclusion, the present study reveals that z-guggulsterone inhibits angiogenesis by suppressing the VEGF-VEGF-R2-Akt signaling axis. Together, our results provide compelling rationale for further preclinical and clinical investigation of z-guggulsterone for its efficacy against prostate cancer.

• Authors: Dong Xiao, Shivendra V Singh
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 1 Pg. 171-80 (Jan 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18202020 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Angiogenesis Inhibitors
• Drug Combinations
• Intercellular Signaling Peptides and Proteins
• Laminin
• Pregnenediones
• Protein Kinase Inhibitors
• Proteoglycans
• matrigel
• Collagen
• pregna-4,17-diene-3,16-dione
• Vascular Endothelial Growth Factor Receptor-2
• Proto-Oncogene Proteins c-akt

Topics

• Angiogenesis Inhibitors (chemistry, pharmacology)
• Animals
• Cell Movement (drug effects)
• Cells, Cultured
• Collagen (metabolism)
• Commiphora (chemistry)
• Drug Combinations
• Endothelial Cells (cytology, drug effects, metabolism)
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Laminin (metabolism)
• Male
• Medicine, Ayurvedic
• Mice
• Molecular Structure
• Pregnenediones (chemistry, pharmacology)
• Prostatic Neoplasms (metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Proteoglycans (metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Umbilical Cord (cytology, drug effects, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)
• Xenograft Model Antitumor Assays