title: Inhibition of B16-BL6 melanoma lung colonies by semisynthetic sulfaminoheparosan sulfates from E. coli K5 polysaccharide.
abstract: Heparin (H), heparan sulfate (HS), and related glycosaminoglycans can inhibit cancer cell invasion, possibly due to their ability to interact with vascular growth factors, adhesion molecules, endoglycosidases, and signaling proteins, in addition to the well-known effects on the clotting system. We evaluated the antitumor activity of a series of semisynthetic sulfaminoheparosan sulfates (SAHSs) with different degree and distribution of sulfates, obtained by chemical modifications of the E. coli K5 polysaccharide, namely type A, B, and C compounds. B16-BL6 melanoma cells (10 5 cells/mouse) were injected intravenously (i.v.) in a lateral tail vein of C57BL6 mice at a dose of 0.5 mg/ mouse together with test compounds. Tumor lung nodules were significantly reduced as compared with controls only by H (95.5 +/- 1.0% inhibition), SAHS-2 (84.2 +/- 5.0% inhibition), and SAHS-4 (91.1 +/- 4.2% inhibition), among compounds tested. SAHS-2 and SAHS-4 are type B compounds, with a sulfate/carboxylate ratio similar to that of H. A typical mammalian HS showed only 54.8% inhibition. Supersulfated low-molecular-weight heparin and heparan sulfate (ssLMWH and ssLMWHS) showed an activity similar to that of unfractionated compounds. H and SAHS-4 inhibited dose dependently B16-BL6 lung colonies, with IC-50 values of 0.05 and 0.1 mg/mouse, respectively. The relationship with ex vivo anticoagulant potency was evaluated by activated partial thromboplastin time (aPTT) on mouse plasma at different time intervals after i.v. injection (0.1 to 0.5 mg/mouse) of the compound. H showed a dose-dependent anticoagulant activity lasting up to 2 hours, whereas SAHS-4 showed a potent anticoagulant effect only at a dose of 0.5 mg/mouse. Accordingly, H but not SAHS-4 consistently inhibited B16-BL6 lung colonies when given 1 hour before tumor cells. SAHS-4 derivatives, with different size and/or affinity depleted of AT binding sites, showed an inhibitory effect on B16-BL6 melanoma similar to that of SAHS-4, suggesting that the greater antitumor effect of H was not due to AT-mediated inhibition of blood clotting. Interactions with other blood inhibitors, such as heparin cofactor II or tissue factor pathway inhibitory protein cannot be ruled out. The better effect of H may be due to persistence in the circulation and/or ability to inhibit tumor neoangiogenesis.
authors.affiliation: Laboratory of Tumor and Vascular Cell Biology, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), Italy. poggi@negrisud.it
authors.forename: Andreina
authors.initials: A
authors.lastname: Poggi
authors.forename: Cosmo
authors.initials: C
authors.lastname: Rossi
authors.forename: Nicola
authors.initials: N
authors.lastname: Casella
authors.forename: Cristiana
authors.initials: C
authors.lastname: Bruno
authors.forename: Luisella
authors.initials: L
authors.lastname: Sturiale
authors.forename: Carla
authors.initials: C
authors.lastname: Dossi
authors.forename: Annamaria
authors.initials: A
authors.lastname: Naggi
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016667:Bacterial Capsules; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006493:Heparin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006497:Heparan Sulfate / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000517:prevention & control* / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010314:Partial Thromboplastin Time; D011135:Polysaccharides, Bacterial / Q000737:chemistry; D013329:Structure-Activity Relationship; D013431:Sulfates
chemical_list: D000925:Anticoagulants; D000970:Antineoplastic Agents; D006493:Heparin; D006497:Heparan Sulfate; D011135:Polysaccharides, Bacterial; D013431:Sulfates; C050673:capsular polysaccharide K5