Selectin blocking activity of a fucosylated chondroitin sulfate glycosaminoglycan from sea cucumber. Effect on tumor metastasis and neutrophil recruitment.
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 beta-D-glucuronic acid residues with 2,4-disulfated alpha-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.
Borsig
Lubor
L
Zurich Center for Integrative Human Physiology and Institute of Physiology, University of Zurich, CH-8057 Zurich, Switzerland.
Wang
Lianchun
L
Cavalcante
Moises C M
MC
Cardilo-Reis
Larissa
L
Ferreira
Paola L
PL
Mourão
Paulo A S
PA
Esko
Jeffrey D
JD
Pavão
Mauro S G
MS
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use; D002236:Carbohydrate Conformation; D002448:Cell Adhesion / Q000187:drug effects; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use; D019041:L-Selectin / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D051379:Mice; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects*; D019007:P-Selectin / Q000378:metabolism*; D010314:Partial Thromboplastin Time; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012616:Sea Cucumbers / Q000737:chemistry*; D013864:Thioglycolates / Q000633:toxicity
D000925:Anticoagulants; D008070:Lipopolysaccharides; D019007:P-Selectin; D013864:Thioglycolates; C517150:fucosylated chondroitin sulfate; D019041:L-Selectin; D006493:Heparin; D002809:Chondroitin Sulfates