Preparation and characterization of 2-deacetyl-3-O-sulfo-heparosan and its antitumor effects via the fibroblast growth factor receptor pathway.
Preparation and characterization of 2-deacetyl-3-O-sulfo-heparosan and its antitumor effects via the fibroblast growth factor receptor pathway.
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DOI：
10.1016/j.ijbiomac.2021.12.098
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发表时间：
2022-01
影响因子：
8.2
通讯作者：
Z. Zha;Yaoyao Liu;Yin-Sha Miao;Shi-Xian Liao;Su-Yan Wang;Huiling Tang;Hongping Yin
中科院分区：
文献类型：
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作者：
Z. Zha;Yaoyao Liu;Yin-Sha Miao;Shi-Xian Liao;Su-Yan Wang;Huiling Tang;Hongping Yin
肝素原是合成肝素的潜在起始化学品，具有由→ 4）β-D-葡萄糖醛酸（GlcA）（1 → 4）-α-D-N-乙酰葡萄糖胺（GlcNAc）（1→）组成的二糖重复单元的线性链。然而，单活性中心硫酸化肝素原的化学酶法合成及其抗肿瘤活性尚未研究。本研究以人3-O-磺基转移酶-1（3-OST-1）为原料，通过N-脱乙酰基化学反应和酶法修饰，制备了2-脱乙酰基-3-O-磺基肝素原（DSH）。DSH的结构表征表明硫酸化成功，硫酸化度为0.87。高效凝胶渗透色谱（HPGPC）分析表明，DSH只有一个对称的峰，分子量为9.6334 × 104 Da。生物学功能研究表明，DSH能抑制肿瘤细胞（A549、HepG 2和HCT 116）的生长，并能诱导A549细胞凋亡。进一步的体外机制研究表明，DSH可能通过JNK信号通路诱导细胞凋亡，而这一过程的上游信号可能是成纤维细胞生长因子受体。这些结果表明，DSH可作为一种潜在的肿瘤治疗药物。
Heparosan, with a linear chain of disaccharide repeating units of → 4) β-D-glucuronic acid (GlcA) (1 → 4)-α-D-N-acetylglucosamine (GlcNAc) (1→, is a potential starting chemical for heparin synthesis. However, the chemoenzymatic synthesis of single-site sulfated heparosan and its antitumor activity have not been studied. In this study, 2-deacetyl-3-O-sulfo-heparosan (DSH) was prepared successively by the N-deacetylation chemical reaction and enzymatic modification of human 3-O-sulfotransferase-1 (3-OST-1). Structural characterization of DSH was shown the success of the sulfation with the sulfation degree of 0.87. High performance gel permeation chromatography (HPGPC) analysis revealed that DSH had only one symmetrical sharp peak with a molecular weight of 9.6334 × 104Da. Biological function studies showed that DSH could inhibit tumor cell (A549, HepG2 and HCT116) viability and induce the apoptosis of A549 cells. Furtherin vitromechanistic studies showed that DSH may induce apoptosis via the JNK signaling pathway, and the upstream signal of this process may be fibroblast growth factor receptors. These results indicated that DSH could be developed as one of a potential chemical for tumor treatment.