Journal Article

Reducing endothelial NOS activation and interstitial fluid pressure with <i>n</i>–3 PUFA offset tumor chemoresistance

Sophie Kornfeld, Caroline Goupille, Sophie Vibet, Stephan Chevalier, Amandine Pinet, Justine Lebeau, François Tranquart, Philippe Bougnoux, Eric Martel, Anne Maurin, Serge Richard, Pascal Champeroux and Karine Mahéo

in Carcinogenesis

Volume 33, issue 2, pages 260-267
Published in print February 2012 | ISSN: 0143-3334
Published online November 2011 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgr274
Reducing endothelial NOS activation and interstitial fluid pressure with n–3 PUFA offset tumor chemoresistance

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The aim of this study was to determine how n–3 polyunsaturated fatty acid (PUFAs) counteracted tumor chemoresistance by restoring a functional vascularization. Rats with chemically induced mammary tumors were divided into two nutritional groups: a control group and a group fed with an n–3 PUFA-enriched diet. Both groups were treated with docetaxel. Functional vascular parameters (ultrasounds, interstitial fluid pressure) were determined for both nutritional groups before (W0) and during docetaxel treatment [every 2 h up to 1 week (W+1) for interstitial fluid pressure, at W+1 for Evans blue extravasation and at W+2 and W+6 for ultrasounds]. In vitro n–3 PUFA-induced changes in endothelial cell migration, permeability and phosphorylation of endothelial nitric oxide synthase were evaluated using human umbilical vein endothelial cells. Whereas docetaxel stabilized tumor growth in the rat control group, it induced a 50% tumor regression in the n–3 PUFA group. Ultrasounds parameters were consistently lower in the n–3 PUFA group at all time points measured, down to ∼50% at W+6. A single dose of docetaxel in the n–3 PUFA group markedly reduced interstitial fluid pressure from 2 h after injection up to W+1 when Evans blue extravasation was increased by 3-fold. A decreased activation of endothelial nitric oxide synthase in tumors of the n–3 PUFA group, and in human umbilical vein endothelial cell cultured with n–3 PUFA, points toward a PUFA-induced disruption of nitric oxide signaling pathway. This normalization of tumor vasculature functions under n–3 PUFA diet indicates that such a supplementation, by improving drug delivery in mammary tumors, could be a complementary clinical strategy to decrease anticancer drug resistance.

Journal Article.  6585 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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