School of Marine Science, Ningbo University, Ningbo 315211, China.
Carbohydr Polym. 2015 Jul 10;125:76-84. doi: 10.1016/j.carbpol.2015.02.069. Epub 2015 Mar 16.
Inhibitors of angiogenesis and tumor metastasis are increasingly emerging as promising agents for cancer therapy. Here, we report λ-carrageenan oligosaccharides (λ-COs), highly-sulfated oligosaccharides acting as a basic fibroblast growth factor (bFGF) antagonist and heparanase inhibitor. λ-COs with degree of polymerization (DP) from 2 to 8 degraded by λ-carrageenase were separated and purified. The structures were identified by mass spectrometry. The activities of λ-COs are closely related with DP. λ-COs showed no cytotoxicity, but inactivated bFGF-induced cell proliferation; among them, λ-carraheptaose showed highest capability. Only λ-carraheptaose can effectively bind to bFGF. Binding kinetics showed that λ-carraheptaose and suramin had different binding modes, i.e., suramin displayed a fast association and fast dissociation, but λ-carraheptaose exhibited a slow association and slow dissociation. In addition, λ-COs showed the highest heparanase inhibitory ability and abolished the endothelial cell invasion. Thus, λ-COs may provide a tool to develop of new carbohydrate-based therapeutics against cancer and angiogenesis.
血管生成和肿瘤转移抑制剂正日益成为癌症治疗的有前途的药物。在这里，我们报告了 λ-卡拉胶低聚糖（λ-COs），作为碱性成纤维细胞生长因子（bFGF）拮抗剂和硫酸乙酰肝素酶抑制剂的高度硫酸化低聚糖。由 λ-卡拉胶酶降解的聚合度（DP）为 2 至 8 的 λ-COs 被分离和纯化。通过质谱鉴定了结构。λ-COs 的活性与其 DP 密切相关。λ-COs 没有细胞毒性，但可使 bFGF 诱导的细胞增殖失活；其中，λ-卡拉庚糖表现出最高的能力。只有 λ-卡拉庚糖才能有效地与 bFGF 结合。结合动力学表明，λ-卡拉庚糖和苏拉明具有不同的结合模式，即苏拉明表现出快速结合和快速解离，而 λ-卡拉庚糖表现出缓慢结合和缓慢解离。此外，λ-COs 表现出最高的肝素酶抑制能力，并能阻止内皮细胞侵袭。因此，λ-COs 可能为开发针对癌症和血管生成的新型基于碳水化合物的治疗方法提供了一种工具。
