Chemically modified, non-anticoagulant heparin derivatives are potent galectin-3 binding inhibitors and inhibit circulating galectin-3-promoted metastasis



Duckworth, Carrie A ORCID: 0000-0001-9992-7540, Guimond, Scott E, Sindrewicz, Paulina, Hughes, Ashley J ORCID: 0000-0001-5432-5271, French, Neil S ORCID: 0000-0002-9376-3482, Lian, Lu-Yun, Yates, Edwin A ORCID: 0000-0001-9365-5433, Pritchard, D Mark ORCID: 0000-0001-7971-3561, Rhodes, Jonathan M ORCID: 0000-0002-1302-260X, Turnbull, Jeremy E ORCID: 0000-0002-1791-754X
et al (show 1 more authors) (2015) Chemically modified, non-anticoagulant heparin derivatives are potent galectin-3 binding inhibitors and inhibit circulating galectin-3-promoted metastasis. ONCOTARGET, 6 (27). pp. 23671-23687.

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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.

Item Type: Article
Uncontrolled Keywords: galectin-3, metastasis, heparin
Subjects: ?? Q1 ??
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Depositing User: Symplectic Admin
Date Deposited: 05 Aug 2015 08:39
Last Modified: 01 Mar 2023 17:46
DOI: 10.18632/oncotarget.4409
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/2015965