Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-53579
Kozlowski, E; Pavão, M S G; Borsig, L (2011). Ascidian dermatan sulfates attenuate metastasis, inflammation and thrombosis by inhibition of P-selectin. Journal of Thrombosis and Haemostasis, 9(9):1807-1815.
View at publisher
Background: Cancer-associated thrombosis and enduring inflammation are strongly associated with cancer progression and metastasis. Heparin is the mostly clinically used anticoagulant/antithrombotic drug, and has recently been shown to exhibit antimetastatic and anti-inflammatory activities that are linked to inhibition of P-selectin and/or L-selectin. P-selectin-mediated platelet–tumor cell and tumor cell–endothelium interactions facilitate the initial steps of metastasis. Objectives and Methods: The aim of the present study was to determine the capacity of dermatan sulfates to inhibit P-selectin and to test their potential to affect thrombosis, inflammation and metastasis in respective experimental mouse models. Results: Two dermatan sulfates isolated from the ascidians Styela plicata and Phallusia nigra, composed of the same disaccharide core structure (IdoA2-GalNAc)n, but sulfated at carbon 4 or 6 of the GalNAc, respectively, have opposed heparin cofactor II (HCII) activities and are potent inhibitors of P-selectin. The ascidian dermatan sulfates effectively attenuated metastasis of both MC-38 colon carcinoma and B16-BL6 melanoma cells and the infiltration of inflammatory cells in a thioglycollate peritonitis mouse model. Moreover, both glycosaminoglycans reduced thrombus size in an FeCl3-induced arterial thrombosis model, irrespective of their HCII activities. The analysis of arterial thrombi demonstrated markedly reduced platelet deposition after dermatan sulfate treatment, suggesting that the glycosaminoglycan inhibited P-selectin and thereby the binding of activated platelets during thrombus formation. Conclusions: Collectively, these findings provide evidence that specific inhibition of P-selectin represents a potential therapeutic target in thrombosis, inflammation and metastasis, and that ascidian dermatan sulfates may serve as antiselectin agents.
28 downloads since deposited on 16 Jan 2012
12 downloads since 12 months
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
04 Faculty of Medicine > Center for Integrative Human Physiology
|Dewey Decimal Classification:||570 Life sciences; biology
610 Medicine & health
|Deposited On:||16 Jan 2012 08:51|
|Last Modified:||07 Dec 2013 08:17|
Users (please log in): suggest update or correction for this item
Repository Staff Only: item control page