title: Reducing endothelial NOS activation and interstitial fluid pressure with n-3 PUFA offset tumor chemoresistance.
abstract: 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 (W(0)) 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.
authors: INSERM U921 Nutrition, Croissance et Cancer Université François Rabelais, Tours, France.
authors: Sophie
authors: S
authors: Kornfeld
authors: Caroline
authors: C
authors: Goupille
authors: Sophie
authors: S
authors: Vibet
authors: Stephan
authors: S
authors: Chevalier
authors: Amandine
authors: A
authors: Pinet
authors: Justine
authors: J
authors: Lebeau
authors: François
authors: F
authors: Tranquart
authors: Philippe
authors: P
authors: Bougnoux
authors: Eric
authors: E
authors: Martel
authors: Anne
authors: A
authors: Maurin
authors: Serge
authors: S
authors: Richard
authors: Pascal
authors: P
authors: Champeroux
authors: Karine
authors: K
authors: Mahéo
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004396:Coloring Agents; D018450:Disease Progression; D000077143:Docetaxel; D004281:Docosahexaenoic Acids / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015118:Eicosapentaenoic Acid / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005070:Evans Blue; D045604:Extracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D004396:Coloring Agents; D015525:Fatty Acids, Omega-3; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; D000077143:Docetaxel; D004281:Docosahexaenoic Acids; D005070:Evans Blue; D015118:Eicosapentaenoic Acid; D052250:Nitric Oxide Synthase Type III