Ginkgo biloba extract EGb 761 exerts anti-angiogenic effects via activation of tyrosine phosphatases.
The standardised Ginkgo biloba extract EGb 761 (Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany) is one of the most widely used herbal remedies. Indications for this extract range from dementia to peripheral vascular disease, based on well-documented vascular effects. Surprisingly, the actions of EGb 761 on angiogenesis as a function of vascular cells have not been investigated to date. The anti-cancer activity of EGb 761 in vitro and epidemiological data showing reduced risk for ovarian cancer in regular users have prompted us to investigate this issue. We show an anti-angiogenic profile of EGb 761 in vitro (inhibited proliferation, migration and tube formation of endothelial cells) and in vivo in the chicken chorio-allantoic membrane (CAM) assay. An analysis of the underlying mechanisms indicates inhibition of growth factor-induced extracellular signal-regulated kinase (ERK) phosphorylation by EGb 761. Inhibitory effects of EGb 761 on ERK as well as of the upstream kinases map-erk-kinase (MEK) and rapidly growing fibrosarcoma (Raf)-1 could be completely reversed by pre-treatment with sodium vanadate (inhibitor of tyrosine phosphatases). Sodium vanadate also reversed the EGb 761-induced inhibition of endothelial cell migration. Focusing on tyrosine phosphatases upstream of the Raf-MEK-ERK cascade, we identified the tyrosine phosphatase Src homology-2 domain-containing phosphatase 1 (SHP-1) as one target of EGb 761. SHP-1 was rapidly activated by EGb 761, and silencing SHP-1 (siRNA) abrogated reduction of endothelial proliferation by EGb 761. In summary, we identify EGb 761 as a potent anti-angiogenic drug. The underlying mechanism is the activation of protein tyrosine phosphatases, leading to inhibition of the Raf-MEK-ERK pathway. These findings provide a rational basis for using EGb 761 for an additional therapeutic indication: anti-angiogenesis-based tumour prevention and adjuvant therapy.
Koltermann
Anja
A
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.
Liebl
Johanna
J
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.
Fürst
Robert
R
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.
Ammer
Hermann
H
Institute of Pharmacology, Toxicology and Pharmacy, University of Munich, Munich, Germany.
Vollmar
Angelika M
AM
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.
Zahler
Stefan
S
Department of Pharmacy, Pharmaceutical Biology, University of Munich, Munich, Germany.
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002461:Cell Line, Transformed; D004789:Enzyme Activation; D005260:Female; D020441:Ginkgo biloba; D006801:Humans; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D034741:RNA, Small Interfering; D000096983:Ginkgo Extract
D020533:Angiogenesis Inhibitors; D010936:Plant Extracts; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D034741:RNA, Small Interfering; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract