title: Antitumor properties of a new non-anticoagulant heparin analog from the mollusk Nodipecten nodosus: Effect on P-selectin, heparanase, metastasis and cellular recruitment.
abstract: Inflammation and cancer are related pathologies acting synergistically to promote tumor progression. In both, hematogenous metastasis and inflammation, P-selectin participates in interactions involving tumor cells, platelets, leukocytes and endothelium. Heparin has been shown to inhibit P-selectin and as a consequence it blunts metastasis and inflammation. Some heparin analogs obtained from marine invertebrates are P-selectin inhibitors and do not induce bleeding effects. The present work focuses on the P-selectin blocking activity of a unique heparan sulfate (HS) from the bivalve mollusk Nodipecten nodosus. Initially, we showed that the mollusk HS inhibited LS180 colon carcinoma cell adhesion to immobilized P-selectin in a dose-dependent manner. In addition, we demonstrated that this glycan attenuates leukocyte rolling on activated endothelium and inflammatory cell recruitment in thioglycollate-induced peritonitis in mice. Biochemical analysis indicated that the invertebrate glycan also inhibits heparanase, a key player in cell invasion and metastasis. Experimental metastasis of Lewis lung carcinoma cells was drastically attenuated by the mollusk HS through a mechanism involving inhibition of platelet-tumor-cell complex formation in blood vessels. These data suggest that the mollusk HS is a potential alternative to heparin for inhibiting P-selectin-mediated events such as metastasis and inflammatory cell recruitment.
authors.affiliation: Laboratório de Bioquímica e Biologia Celular de Glicoconjugados, Programa de Glicobiologia, Instituto de Bioquímica Médica Leopoldo de Meis and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941 913, Brazil.
authors.forename: Angélica Maciel
authors.initials: AM
authors.lastname: Gomes
authors.affiliation: Laboratório de Bioquímica e Biologia Celular de Glicoconjugados, Programa de Glicobiologia, Instituto de Bioquímica Médica Leopoldo de Meis and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941 913, Brazil.
authors.forename: Eliene Oliveira
authors.initials: EO
authors.lastname: Kozlowski
authors.affiliation: Institute of Physiology, University of Zurich and Zurich Center for Integrative Human Physiology, Zurich 8057, Switzerland.
authors.forename: Lubor
authors.initials: L
authors.lastname: Borsig
authors.affiliation: Laboratório de Bioquímica e Biologia Celular de Glicoconjugados, Programa de Glicobiologia, Instituto de Bioquímica Médica Leopoldo de Meis and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941 913, Brazil.
authors.forename: Felipe C O B
authors.initials: FC
authors.lastname: Teixeira
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Haifa 31096, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Laboratório de Bioquímica e Biologia Celular de Glicoconjugados, Programa de Glicobiologia, Instituto de Bioquímica Médica Leopoldo de Meis and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941 913, Brazil mpavao@hucff.ufrj.br.
authors.forename: Mauro S G
authors.initials: MS
authors.lastname: Pavão
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000556:secondary; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000737:chemistry; D006497:Heparan Sulfate / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D036904:Leukocyte Rolling / Q000187:drug effects; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008974:Mollusca; D009368:Neoplasm Transplantation; D019007:P-Selectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099175:Heparanase
chemical_list: D000925:Anticoagulants; D000970:Antineoplastic Agents; D005966:Glucuronidase; D006497:Heparan Sulfate; D019007:P-Selectin; D000099175:Heparanase
keywords: P-selectin; anti-cancer activity; heparanase; mollusk heparan sulfate