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J. Biol. Chem., Vol. 282, Issue 20, 14984-14991, May 18, 2007

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Selectin Blocking Activity of a Fucosylated Chondroitin Sulfate Glycosaminoglycan from Sea Cucumber

EFFECT ON TUMOR METASTASIS AND NEUTROPHIL RECRUITMENT^*

Lubor Borsig¹, Lianchun Wang¹, Moises C. M. Cavalcante^¶, Larissa Cardilo-Reis^¶, Paola L. Ferreira^¶, Paulo A. S. Mourão^¶2, Jeffrey D. Esko^||, and Mauro S. G. Pavão^¶23

From the Zurich Center for Integrative Human Physiology and Institute of Physiology, University of Zurich, CH-8057 Zurich, Switzerland, the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602-4712, the ^¶Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Instituto de Bioquímica Médica, Programa de Glicobiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-590, Brazil, and the ^||Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093

Heparin is an excellent inhibitor of P- and L-selectin binding to the carbohydrate determinant, sialyl Lewis^x. As a consequence of its anti-selectin activity, heparin attenuates metastasis and inflammation. Here we show that fucosylated chondroitin sulfate (FucCS), a polysaccharide isolated from sea cucumber composed of a chondroitin sulfate backbone substituted at the 3-position of the -D-glucuronic acid residues with 2,4-disulfated -L-fucopyranosyl branches, is a potent inhibitor of P- and L-selectin binding to immobilized sialyl Lewis^x and LS180 carcinoma cell attachment to immobilized P- and L-selectins. Inhibition occurs in a concentration-dependent manner. Furthermore, FucCS was 4–8-fold more potent than heparin in the inhibition of the P- and L-selectin-sialyl Lewis^x interactions. No inhibition of E-selectin was observed. FucCS also inhibited lung colonization by adenocarcinoma MC-38 cells in an experimental metastasis model in mice, as well as neutrophil recruitment in two models of inflammation (thioglycollate-induced peritonitis and lipopolysaccharide-induced lung inflammation). Inhibition occurred at a dose that produces no significant change in plasma activated partial thromboplastin time. Removal of the sulfated fucose branches on the FucCS abolished the inhibitory effect in vitro and in vivo. Overall, the results suggest that invertebrate FucCS may be a potential alternative to heparin for blocking metastasis and inflammatory reactions without the undesirable side effects of anticoagulant heparin.

Received for publication, November 14, 2006 , and in revised form, March 19, 2007.

^* This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo Pesquisa do Estado do Rio de Janeiro, and Fundação Ari Frauzino (FAF)/Instituto de Ciências Biomêdicas-Universidade Federal do Rio de Janeiro; by National Institutes of Health Fogarty International Center Grant R03 TW05775 (to M. S. G. P.); by Swiss National Science Foundation Grant 3100A0-100303 (to L. B.); and by National Institutes of Health Grants HL57345 and CA11227 (to J. D. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Research fellows from Conselho Nacional de Desenvolvimento Científico e Tecnológico.

³ To whom correspondence should be addressed. Tel.: 55-21-2562-2093; Fax: 55-21-2562-2090; E-mail: mpavao{at}hucff.ufrj.br.

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