title: Chemically modified, non-anticoagulant heparin derivatives are potent galectin-3 binding inhibitors and inhibit circulating galectin-3-promoted metastasis.
abstract: Concentrations of circulating galectin-3, a metastasis promoter, are greatly increased in cancer patients. Here we show that 2- or 6-de-O-sulfated, N-acetylated heparin derivatives are galectin-3 binding inhibitors. These chemically modified heparin derivatives inhibited galectin-3-ligand binding and abolished galectin-3-mediated cancer cell-endothelial adhesion and angiogenesis. Unlike standard heparin, these modified heparin derivatives and their ultra-low molecular weight sub-fractions had neither anticoagulant activity nor effects on E-, L- or P-selectin binding to their ligands nor detectable cytotoxicity. Intravenous injection of such heparin derivatives (with cancer cells pre-treated with galectin-3 followed by 3 subcutaneous injections of the derivatives) abolished the circulating galectin-3-mediated increase in lung metastasis of human melanoma and colon cancer cells in nude mice. Structural analysis using nuclear magnetic resonance and synchrotron radiation circular dichroism spectroscopies showed that the modified heparin derivatives bind to the galectin-3 carbohydrate-recognition domain. Thus, these chemically modified, non-anticoagulant, low-sulfated heparin derivatives are potent galectin-3 binding inhibitors with substantial potential as anti-metastasis/cancer drugs.
authors.affiliation: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Duckworth
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Guimond
authors.affiliation: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Paulina
authors.initials: P
authors.lastname: Sindrewicz
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.|Diamond Light Source Ltd, Harwell Innovation Campus, Didcot, United Kingdom.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Hughes
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Neil S
authors.initials: NS
authors.lastname: French
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Lu-Yun
authors.initials: LY
authors.lastname: Lian
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Yates
authors.affiliation: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: D Mark
authors.initials: DM
authors.lastname: Pritchard
authors.affiliation: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Rhodes
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Turnbull
authors.affiliation: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Lu-Gang
authors.initials: LG
authors.lastname: Yu
mesh_terms: D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D003110:Colonic Neoplasms / Q000473:pathology; D005260:Female; D037502:Galectin 3 / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D037161:Galectins; D006493:Heparin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008279:Magnetic Resonance Imaging; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000187:drug effects
chemical_list: D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C428445:LGALS3 protein, human; D006493:Heparin
keywords: galectin-3; heparin; metastasis