Selectin Blocking Activity of a Fucosylated Chondroitin Sulfate Glycosaminoglycan from Sea Cucumber: EFFECT ON TUMOR METASTASIS AND NEUTROPHIL RECRUITMENT

• Published in: The Journal of biological chemistry 2007-05, Vol.282 (20), p.14984-14991
• Main Authors: Borsig, Lubor, Wang, Lianchun, Cavalcante, Moises C.M, Cardilo-Reis, Larissa, Ferreira, Paola L, Mourão, Paulo A.S, Esko, Jeffrey D, Pavão, Mauro S.G
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Anticoagulants - pharmacology; Anticoagulants - therapeutic use; Carbohydrate Conformation; Cell Adhesion - drug effects; Chondroitin Sulfates - chemistry; Chondroitin Sulfates - pharmacology; Chondroitin Sulfates - therapeutic use; Disease Models, Animal; Dose-Response Relationship, Drug; Heparin - pharmacology; Heparin - therapeutic use; Holothurioidea; L-Selectin - metabolism; Lipopolysaccharides - toxicity; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Marine; Mice; Neoplasm Metastasis; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Neutrophil Infiltration - drug effects; P-Selectin - metabolism; Partial Thromboplastin Time; Peritonitis - chemically induced; Peritonitis - drug therapy; Peritonitis - metabolism; Peritonitis - pathology; Pneumonia - chemically induced; Pneumonia - drug therapy; Pneumonia - metabolism; Pneumonia - pathology; Sea Cucumbers - chemistry; Thioglycolates - toxicity
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M610560200

Heparin is an excellent inhibitor of P- and L-selectin binding to the carbohydrate determinant, sialyl Lewisx. 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 β-D-glucuronic acid residues with 2,4-disulfated α-L-fucopyranosyl branches, is a potent inhibitor of P- and L-selectin binding to immobilized sialyl Lewisx 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 Lewisx 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.