The cytoprotective drug amifostine modifies both expression and activity of the pro-angiogenic factor VEGF-A

BMC Medicine

Research Article

R Sinisi¹  M Zanda¹  HR Rezvani²  F Mazurier²  S North³  A Bikfalvi³  M Bouchecareilh³  S Dedieu³  X Canron³  M Moenner³ 

[1] CNR, I-20131, Milano, Italy;Inserm, U 876, F33000, Bordeaux, France;University of Bordeaux 2, F-33000, Bordeaux, France;Inserm, U920, F-33400, Talence, France;University of Bordeaux 1, F-33400, Talence, France;

关键词: MCF7 Cell;    Unfold Protein Response;    Enhance Green Fluorescent Protein;    Amifostine;    Bovine Serum Albumine;   

DOI  :  10.1186/1741-7015-8-19

 received in 2010-01-07, accepted in 2010-03-24,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundAmifostine (WR-2721, delivered as Ethyol®) is a phosphorylated aminothiol compound clinically used in addition to cis-platinum to reduce the toxic side effects of therapeutic treatment on normal cells without reducing their efficacy on tumour cells. Its mechanism of action is attributed to the free radical scavenging properties of its active dephosphorylated metabolite WR-1065. However, amifostine has also been described as a potent hypoxia-mimetic compound and as a strong p53 inducer; both effects are known to potently modulate vascular endothelial growth factor (VEGF-A) expression. The angiogenic properties of this drug have not been clearly defined.MethodsCancer 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.ResultsWe 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-1α. 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.ConclusionsTaken 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.

【 授权许可】

Unknown   
© Dedieu et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.