Isogambogenic acid inhibits tumour angiogenesis by suppressing Rho GTPases and vascular endothelial growth factor receptor 2 signalling pathway.
Isogambogenic acid (iso-GNA) is a well-known herbal medicine extracted from Garcinia hanburyi. Although it is thought to have anti-tumour effects, its function is still unknown. This study carried out in vitro and in vivo evaluations of the anti-tumour and anti-angiogenic activity of iso-GNA and underlying mechanisms. A standard methyl thiazolyl tetrazolium assay showed that iso-GNA was more effective in inhibiting the proliferation of human umbilical vascular endothelial cells than A549 cancer cells. Iso-GNA demonstrated potent anti-angiogenic activity and low toxicity at appropriate concentrations in zebrafish embryos. In a xenograft nude mouse model of lung tumour, iso-GNA effectively inhibited tumour growth and tumour angiogenesis. Iso-GNA suppressed neovascularization of implanted matrigel plugs in vivo and inhibited vascular endothelial growth factor (VEGF)-induced microvessel sprouting from mouse aortic rings ex vivo. Iso-GNA inhibited VEGF-induced migration, invasion, and tube formation in vitro and affected cytoskeletal rearrangement in human umbilical vascular endothelial cells. The results show that iso-GNA suppressed angiogenesis-mediated tumour growth by targeting VEGFR2, Akt, mitogen-activated protein kinase, Rho GTPase, vascular endothelium-cadherin, and focal adhesion kinase signalling pathways. Together, these data suggest that iso-GNA inhibits angiogenesis and may be a viable drug candidate in anti-angiogenesis and anti-cancer therapies.
Sichuan University, Chengdu, China.
Yi
Y
Fan
Aihua
A
Peng
Shichao
S
He
Ximing
X
Shao
Chunlai
C
Nie
Lijuan
L
Chen
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D014966:Xanthenes; D044004:Xanthones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010936:Plant Extracts; D013729:Terpenes; D042461:Vascular Endothelial Growth Factor A; D014966:Xanthenes; D044004:Xanthones; C045863:neo-gambogic acid; D040301:Vascular Endothelial Growth Factor Receptor-2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020741:rho GTP-Binding Proteins