A disaccharide precursor of sialyl Lewis X inhibits metastatic potential of tumor cells.
Clustered presentation of sialyl Lewis X (sLe(X)) on tumor cell mucins is thought to facilitate metastasis through binding to selectin adhesion receptors expressed on platelets, leukocytes and endothelial cells. Thus, interfering with sLe(X) assembly might provide a chemotherapeutic method for treating metastatic disease. Prior studies have shown that peracetylated disaccharides can act in cells as substrates for the assembly of oligosaccharides related to sLe(X) synthesis, and the assembly of oligosaccharides on the disaccharides diverts the assembly of sLe(X) from endogenous cell surface glycoconjugates. Here, we show that treatment of cultured human adenocarcinoma cells with micromolar concentrations of the peracetylated disaccharide, (Ac)(6)GlcNAcbeta1,3Galbeta-O-naphthalenemethanol (AcGnG-NM) reduces the expression of sLe(X) and diminishes binding in vitro to selectin-coated dishes, thrombin-activated platelets, and tumor necrosis factor alpha-activated endothelial cells. Altering glycosylation in this way significantly reduced the ability of tumor cells to distribute to the lungs of wild-type mice over a 3-h period after i.v. injection. No significant difference in biodistribution was noted after the injection of AcGnG-NM-treated tumor cells into P-selectin deficient mice, although the extent of lung seeding was reduced compared with that in wild-type mice. In vitro, we demonstrate that normal mouse platelets, but not P-selectin-deficient platelets, bound to control tumor cells and protected them from leukocyte-mediated cytolysis. Conversely, treatment of tumor cells with disaccharide markedly reduced the ability of normal platelets to protect them from cytolysis. Finally, in an experimental metastasis model, we show that treatment of tumor cells with the disaccharide markedly reduced their lung colonization potential after injection into severe combined immunodeficient mice. These findings suggest that this compound may represent a novel class of chemotherapeutic agents for prevention and treatment of metastatic disease.
Fuster
Mark M
MM
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Diego, California, 92103-0687, USA.
Brown
Jillian R
JR
Wang
Lianchun
L
Esko
Jeffrey D
JD
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018395:CA-19-9 Antigen; D002240:Carbohydrate Sequence; D002448:Cell Adhesion / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004187:Disaccharides / Q000493:pharmacokinetics / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009844:Oligosaccharides / Q000378:metabolism*; D000080506:Sialyl Lewis X Antigen; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
C475838:(Ac)(6)GlcNAcbeta1,3Galbeta-O-naphthalenemethanol; D018395:CA-19-9 Antigen; D004187:Disaccharides; D005732:Gangliosides; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; C064564:sialyl Le(a) ganglioside