title: Sulfated hexasaccharides attenuate metastasis by inhibition of P-selectin and heparanase.
abstract: Development of compounds that target both heparanase and selectins is emerging as a promising approach for cancer therapy. Selectins are vascular cell adhesion molecules that mediate tumor cell interactions with platelets, leukocytes, and the vascular endothelium. Heparanase is an endoglycosidase that degrades heparan sulfate in the tumor microenvironment, cell surfaces, and vessel wall. Acting together, these molecules facilitate tumor cell arrest, extravasation, and metastasis. Here, we report the preparation of novel semisynthetic sulfated tri mannose C-C-linked dimers (STMCs) endowed with heparanase and selectin inhibitory activity. The P-selectin specificity of the STMC was defined by the anomeric linkage of the C-C bond. This STMC hexasaccharide is an effective inhibitor of P-selectin in vivo. We show that selective inhibition of heparanase attenuates metastasis in B16-BL6 melanoma cells, expressing high levels of this endoglycosidase, but has no effect on the metastasis of MC-38 carcinoma cells that express little or no heparanase activity. P-selectin-specific STMC attenuated metastasis in both animal models, indicating that inhibition of tumor cell interaction with the vascular endothelium is critical for cancer dissemination. Thus, the small size, the stability of the C-C bond, and the chemically defined structure of the newly generated STMCs make them superior to heparin derivatives and signify STMCs as valuable candidates for further evaluation.
authors.affiliation: Zürich Center for Integrative Human Physiology, Institute of Physiology, University of Zürich, Zürich, Switzerland. lborsig@access.uzh.ch
authors.forename: Lubor
authors.initials: L
authors.lastname: Borsig
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Rivka
authors.initials: R
authors.lastname: Ishai-Michaeli
authors.forename: Giangiacomo
authors.initials: G
authors.lastname: Torri
authors.forename: Elena
authors.initials: E
authors.lastname: Vismara
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006026:Glycoside Hydrolases / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009844:Oligosaccharides / Q000494:pharmacology*; D019007:P-Selectin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013431:Sulfates / Q000494:pharmacology*; D059016:Tumor Microenvironment; D000099175:Heparanase
chemical_list: D000970:Antineoplastic Agents; D005966:Glucuronidase; D006026:Glycoside Hydrolases; D009844:Oligosaccharides; D019007:P-Selectin; D013431:Sulfates; D000099175:Heparanase