School of Pharmacy, University of Tasmania, Hobart, TAS, Australia.
Integr Biol (Camb). 2014 Jan;6(1):90-9. doi: 10.1039/c3ib40206a.
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.
肝素、未分级肝素 (UFH) 和低分子量肝素 (LMWH) 是抗凝和非抗凝低聚糖的不均匀混合物。除了众所周知的抗凝作用外，肝素还显示出介导广泛的非抗凝作用，包括细胞生长的调节。然而，关于它们对细胞增殖的影响，已有相互矛盾的结果报告，一些研究表明具有抗增殖作用，而另一些则表明具有促增殖作用。本研究调查了 UFH 和 LMWH（依诺肝素和达肝素）存在时人结肠上皮癌细胞的增殖。在我们的实验设置中，所有肝素都导致细胞生长呈剂量依赖性降低，这与细胞周期阻滞在 G₁ 期的诱导密切相关，并且与细胞活力的显著变化无关。还评估了通过离子交换色谱获得的依诺肝素的 14 种不同低聚糖对细胞增殖的影响。令人惊讶的是，只有两种低聚糖表现出独特的抗增殖作用，而大多数低聚糖实际上刺激了增殖。有趣的是，没有任何抗凝活性的最小低聚糖表现出最强的抗增殖作用。值得注意的是，肝素目前仅根据其抗凝活性进行标准化，而不是根据其他非抗凝特性进行标准化。我们的结果表明，由于材料和制备方法的不同来源，肝素非抗凝低聚糖组成的细微差异有可能导致不同的作用，并强调需要对非抗凝活性进行额外的表征。
