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  3. Oligosaccharides from fucosylated glycosaminoglycan prevent breast cancer metastasis in mice by inhibiting heparanase activity and angiogenesis

Oligosaccharides from fucosylated glycosaminoglycan prevent breast cancer metastasis in mice by inhibiting heparanase activity and angiogenesis

  • Pharmacol Res. 2021 Apr;166:105527. doi: 10.1016/j.phrs.2021.105527.
Lutan Zhou 1,  Ronghua Yin 2,  Na Gao 2,  Huifang Sun 3,  Dingyuan Chen 3,  Ying Cai 3,  Lin Ren 4,  Lian Yang 4,  Zhili Zuo 5,  Hongbin Zhang 6,  Jinhua Zhao 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China.
  • 2 School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China.
  • 3 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
  • 5 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China. Electronic address: zuozhili@mail.kib.ac.cn.
  • 6 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China. Electronic address: zhanghb@ynu.edu.cn.
  • 7 School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China. Electronic address: zhao.jinhua@yahoo.com.
PMID: 33667689 DOI: 10.1016/j.phrs.2021.105527
Abstract

The invasion and metastasis of tumor cells are the hallmarks of malignant diseases and the greatest obstacle to overcome. Heparanase-mediated degradation of heparan sulfate (HS) is the critical process for tumor angiogenesis and metastasis, therefore, heparanase become an attractive target for Cancer research. Herein, we reported a native fucosylated glycosaminoglycan (nHG) extracted from sea cucumber Holothuria fuscopunctata and a depolymerized nHG (dHG) and its contained oligosaccharides (hs17, hs14, hs11, hs8 and hs5), acting as heparanase inhibitors. nHG and its derivatives have the ability to bind with heparanase directly, leading to significant inhibition of heparanase activity. Moreover, their apparent binding affinity to heparanase was comparable to their inhibitory effect, which was elevated along with the increase of chain length, similar to the effect of heparins. In addition, oligosaccharides inhibited the migration and invasion of 4T1 mammary carcinoma cells and human umbilical vein endothelial cells (HUVECs) and also suppressed tube formation in Matrigel matrix and angiogenesis in the chick chorioallantoic membrane (CAM) assay. In the metastatic mouse model, oligosaccharides exhibited practical antimetastatic effects on 4T1 mammary carcinoma cells. According to the reported anticoagulant activity and the low bleeding tendency of dHG and its oligosaccharides, the use of the oligosaccharides may lead to better effects on tumor patients with thrombosis tendency.

Keywords

Angiogenesis; Heparanase; Metastasis; Oligosaccharides.

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