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

Carrie A Duckworth,D Mark Pritchard,Paulina Sindrewicz,Jonathan M Rhodes,Edwin A Yates,Lu-Yun Lian,Lu-Gang Yu,Jeremy E Turnbull,Neil S French,Ashley J Hughes,Scott E Guimond

doi:10.18632/oncotarget.4409

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

Carrie A Duckworth, D Mark Pritchard + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.4409

Copy DOI

Journal: Oncotarget	Publication Date: Jun 23, 2015
Citations: 43	License type: cc-by

Affiliation: University of Liverpool

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.

Highlights

Metastasis is the main cause of cancer mortality and is associated with greater than 90% of all cancer-related deaths
The galectin-3-MUC1/4 interaction induces MUC1/4 cell surface polarization and results in the exposure of smaller cell surface adhesion molecules leading to increased adhesion of disseminating tumor cells to the vascular endothelium, and increased aggregation of cancer cells resulting in the potential formation of circulating tumor emboli [9, 10]
Twenty-four heparin derivatives produced by selective chemical modification and size fractionation (Supplementary Table S3) were screened for their effects on galectin-3 binding to the TF-expressing asialo-fetuin (Supplementary Fig. S2). 2 or 6-de-sulfated, N-acetylated heparin derivatives (E and F) and 2- and 6-de-O-sulfated, N-sulfated heparin (G) produced significant inhibition of galectin-3 binding to asialo-fetuin (Fig. 1A–1F)

Summary

Introduction

Metastasis is the main cause of cancer mortality and is associated with greater than 90% of all cancer-related deaths. Recent studies have shown that increased concentrations www.impactjournals.com/oncotarget of circulating galectin-3 promote dissemination of tumour cell metastatic spread to remote sites [8,9,10,11,12,13,14,15,16,17]. These effects are partly attributable to its interaction with the oncofetal Galβ1, 3GalNAcα- (TF) antigen expressed on the cancer cell membrane-associated mucin proteins MUC1 [18] and MUC4 [12]. Several have shown promise in animal models and are currently undergoing clinical trials (e.g. GMCT-01 and GRMD-02; GCS-100) [17]

Methods

Results

Conclusion