No abstract

In tumor development, the degradation of heparan sulfate (HS) by heparanase (HPSE) is associated with cell-surface and extracellular matrix remodeling as well as the release of HS-bound signaling molecules, allowing cancer cell migration, invasion and angiogenesis. Because of their structural similarity with HS, sulfated polysaccharides are considered a promising source of molecules to control these activities. In this study, we used a depolymerisation method for producing λ-carrageenan oligosaccharides (λ-CO), with progressive desulfation over time. These were then used to investigate the influence of polymeric chain length and degree of sulfation (DS) on their anti-HPSE activity. The effects of these two features on λ-CO anticoagulant properties were also investigated to eliminate a potential limitation on the use of a candidate λ-CO as a chemotherapeutic agent. HPSE inhibition was mainly related to the DS of λ-CO, however this correlation was not complete. On the other hand, both chain length and DS modulated λ-CO activity for factor Xa and thrombin IIa inhibition, two enzymes that are involved in the coagulation cascade, and different mechanisms of inhibition were observed. A λ-carrageenan oligosaccharide of 5.9 KDa was identified as a suitable anticancer candidate because it displayed one of the lowest anticoagulant properties among the λ-CO produced, while showing a remarkable inhibitory effect on MDA-MB-231 breast cancer cell migration.

(1) Background: Brown and red algal sulfated polysaccharides have been widely described as anticoagulant agents. However, data on green algae, especially on the Ulva genus, are limited. This study aimed at isolating ulvan from the green macroalga Ulva rigida using an acid- and solvent-free procedure, and investigating the effect of sulfate content on the anticoagulant activity of this polysaccharide. (2) Methods: The obtained ulvan fraction was chemically sulfated, leading to a doubling of the polysaccharide sulfate content in a second ulvan fraction. The potential anticoagulant activity of both ulvan fractions was then assessed using different assays, targeting the intrinsic and/or common (activated partial thromboplastin time), extrinsic (prothrombin time), and common (thrombin time) pathways, and the specific antithrombin-dependent pathway (anti-Xa and anti-IIa), of the coagulation cascade. Furthermore, their anticoagulant properties were compared to those of commercial anticoagulants: heparin and Lovenox®. (3) Results: The anticoagulant activity of the chemically-sulfated ulvan fraction was stronger than that of Lovenox® against both the intrinsic and extrinsic coagulation pathways. (4) Conclusion: The chemically-sulfated ulvan fraction could be a very interesting alternative to heparins, with different targets and a high anticoagulant activity.