• Open Access

Ginkgo biloba extract EGb® 761 exerts anti-angiogenic effects via activation of tyrosine phosphatases

Authors


Correspondence to: Stefan ZAHLER,
Department of Pharmacy, Pharmaceutical Biology, University of Munich,
Butenandtstr. 5–13, 81377 Munich, Germany.
Tel.: +49-89-2180-77196 Fax: +49-89-2180-77170
E-mail: stefan.zahler@cup.uni-muenchen.de

Abstract

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.

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