title: Modified heparin inhibits P-selectin-mediated cell adhesion of human colon carcinoma cells to immobilized platelets under dynamic flow conditions.
abstract: Accumulating evidence indicates that the formation of tumor cell platelet emboli complexes in the blood stream is a very important step during metastases and that the anti-metastasis effects of heparin are partially due to a blockade of P-selectin on platelets. In this study, heparin and chemically modified heparins were tested as inhibitors of three human colon carcinoma cell lines (COLO320, LS174T, and CW-2) binding to P-selectin, adhering to CHO cells expressing a transfected human P-selectin cDNA, and adhering to surface-anchored platelets expressing P-selectin under static and flow conditions. The aim was to screen for heparin derivatives with high anti-adhesion activity but negligible anticoagulant activity. In this study, four modified heparins with high anti-adhesion activity were identified including RO-heparin, CR-heparin, 2/3ODS-heparin, and N/2/3DS-heparin. NMR analysis proved the reliability of structure of the four modified heparins. Our findings suggested that the 6-O-sulfate group of glucosamine units in heparin is critical for the inhibition of P-selectin-mediated tumor cell adhesion. Heparan sulfate-like proteoglycans on these tumor cell surfaces are implicated in adhesion of the tumor cells to P-selectin. Some chemically modified heparins with low anticoagulant activities, such as 2/3ODS-heparin, may have potential value as therapeutic agents that block P-selectin-mediated cell adhesion and prevent tumor metastasis.
authors.affiliation: Institute of Genetics and Cytology, School of Life Science, Northeast Normal University, Changchun, 130024, Jilin, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Guihua
authors.initials: G
authors.lastname: Tai
authors.forename: Yanguang
authors.initials: Y
authors.lastname: Gao
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Baiqu
authors.initials: B
authors.lastname: Huang
authors.forename: Yifa
authors.initials: Y
authors.lastname: Zhou
authors.forename: Shui
authors.initials: S
authors.lastname: Hao
authors.forename: Xianlu
authors.initials: X
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry* / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism*; D016466:CHO Cells; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006493:Heparin / Q000031:analogs & derivatives* / Q000378:metabolism*; D019763:Heparin Lyase / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D013314:Stress, Mechanical; D013552:Swine
chemical_list: D000925:Anticoagulants; D019812:Heparan Sulfate Proteoglycans; D008024:Ligands; D019007:P-Selectin; D006493:Heparin; D019763:Heparin Lyase