title: Identification of pro- and anti-proliferative oligosaccharides of heparins.
abstract: Heparins, unfractionated heparin (UFH) and low molecular weight heparins (LMWHs), are heterogeneous mixtures of anticoagulant and non-anticoagulant oligosaccharides. In addition to their well-known anticoagulant effect, heparins have shown to mediate a wide range of non-anticoagulant effects, including the modulation of cellular growth. However, contradictory results have been reported with regard to their effects on cellular proliferation, with some studies suggesting anti-proliferative while others indicating pro-proliferative effects. This study investigated the proliferation of human colonic epithelial cancer cells in the presence of UFH and LMWHs (enoxaparin and dalteparin). In our experimental setting, all heparins caused a dose-dependent reduction in cellular growth, which correlated well with the induction of cell cycle arrest in the G₁ phase and which was not associated with significant changes in cell viability. The effects on cellular proliferation of 14 different oligosaccharides of enoxaparin obtained through ion-exchange chromatography were also assessed. Surprisingly, only two oligosaccharides showed distinctive anti-proliferative effects while the majority of oligosaccharides actually stimulated proliferation. Interestingly, the smallest oligosaccharide devoid of any anticoagulant activity showed the strongest anti-proliferative effect. Notably, heparins are currently standardised only according to their anticoagulant activity but not based on other non-anticoagulant properties. Our results indicate that slight differences in the composition of heparins' non-anticoagulant oligosaccharides, due to different origins of material and preparation methods, have the potential to cause diverse effects and highlight the need for additional characterisation of non-anticoagulant activities.
authors: School of Pharmacy, University of Tasmania, Hobart, TAS, Australia. nguven@utas.edu.au.
authors: Qi Ying
authors: QY
authors: Lean
authors: Rahul P
authors: RP
authors: Patel
authors: Niall
authors: N
authors: Stewart
authors: Sukhwinder Singh
authors: SS
authors: Sohal
authors: Nuri
authors: N
authors: Gueven
mesh_terms: D002452:Cell Count; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000502:physiology; D002852:Chromatography, Ion Exchange / Q000379:methods; D017985:Dalteparin / Q000737:chemistry* / Q000494:pharmacology; D017984:Enoxaparin / Q000737:chemistry* / Q000494:pharmacology; D005434:Flow Cytometry; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D009844:Oligosaccharides / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D017984:Enoxaparin; D009844:Oligosaccharides; D017985:Dalteparin