%0 Journal Article
%T The cytoprotective drug amifostine modifies both expression and activity of the pro-angiogenic factor VEGF-A
%A S Dedieu
%A X Canron
%A HR Rezvani
%A M Bouchecareilh
%A F Mazurier
%A R Sinisi
%A M Zanda
%A M Moenner
%A A Bikfalvi
%A S North
%J BMC Medicine
%D 2010
%I BioMed Central
%R 10.1186/1741-7015-8-19
%X Cancer cell lines and endothelial cells were used in culture and treated with Amifostine in order to study (i) the expression of angiogenesis related genes and proteins and (ii) the effects of the drug on VEGF-A induced in vitro angiogenesis.We demonstrated that the treatment of several human cancer cell lines with therapeutical doses of WR-1065 led to a strong induction of different VEGF-A mRNA isoforms independently of HIF-1¦Á. VEGF-A induction by WR-1065 depends on the activation of the eIF2alpha/ATF4 pathway. This up-regulation of VEGF-A mRNA was accompanied by an increased secretion of VEGF-A proteins fully active in stimulating vascular endothelial cells (EC). Nevertheless, direct treatment of EC with amifostine impaired their ability to respond to exogenous VEGF-A, an effect that correlated to the down-regulation of VEGFR-2 expression, to the reduction in cell surface binding of VEGF-A and to the decreased phosphorylation of the downstream p42/44 kinases.Taken together, our results indicate that amifostine treatment modulates tumour angiogenesis by two apparently opposite mechanisms - the increased VEGF-A expression by tumour cells and the inhibition of EC capacity to respond to VEGF-A stimulation.First developed for its cytoprotective properties against radiation, amifostine is now approved by the US Food and Drug Administration for clinical use as a cytoprotector in several anti-cancer therapies [1]. Amifostine, also called Ethyol£¿, is a phosphorylated aminothiol (WR-2721). Its intracellular activity relies on its dephosphorylation by membrane bound alkaline phosphatase [2], thus producing the free thiol WR-1065. WR-1065 acts as a free radical scavenger and is considered to be the effective cytoprotector, affording protection against the toxic side effects of both chemotherapeutic agents and ionizing radiations [3-5]. This cytoprotection has been shown to be mostly effective on normal cells and does not interfere with the efficacy of anticancer treatment in
%U http://www.biomedcentral.com/1741-7015/8/19