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Fucans, but not fucomannoglucuronans, determine the biological activities of sulfated polysaccharides from Laminaria saccharina brown seaweed.

Croci DO, Cumashi A, Ushakova NA, Preobrazhenskaya ME, Piccoli A, Totani L, Ustyuzhanina NE, Bilan MI, Usov AI, Grachev AA, Morozevich GE, Berman AE, Sanderson CJ, Kelly M, Di Gregorio P, Rossi C, Tinari N, Iacobelli S, Rabinovich GA, Nifantiev NE, Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO), Ita - PLoS ONE (2011)

Bottom Line: This effect correlated with a reduction in plasminogen activator inhibitor-1 (PAI-1) levels in L.s.-1.25-treated endothelial cells.The incorporation of L.s.-P or L.s.-1.25, but not L.s.-1.0 into Matrigel plugs containing melanoma cells induced a significant reduction in hemoglobin content as well in the frequency of tumor-associated blood vessels.Moreover, i.p. administrations of L.s.-1.25, as well as L.s.-P, but not L.s.-1.0, resulted in a significant reduction of tumor growth when inoculated into syngeneic mice.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas y Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.

ABSTRACT
Sulfated polysaccharides from Laminaria saccharina (new name: Saccharina latissima) brown seaweed show promising activity for the treatment of inflammation, thrombosis, and cancer; yet the molecular mechanisms underlying these properties remain poorly understood. The aim of this work was to characterize, using in vitro and in vivo strategies, the anti-inflammatory, anti-coagulant, anti-angiogenic, and anti-tumor activities of two main sulfated polysaccharide fractions obtained from L. saccharina: a) L.s.-1.0 fraction mainly consisting of O-sulfated mannoglucuronofucans and b) L.s.-1.25 fraction mainly composed of sulfated fucans. Both fractions inhibited leukocyte recruitment in a model of inflammation in rats, although L.s.-1.25 appeared to be more active than L.s.-1.0. Also, these fractions inhibited neutrophil adhesion to platelets under flow. Only fraction L.s.-1.25, but not L.s.-1.0, displayed anticoagulant activity as measured by the activated partial thromboplastin time. Investigation of these fractions in angiogenesis settings revealed that only L.s.-1.25 strongly inhibited fetal bovine serum (FBS) induced in vitro tubulogenesis. This effect correlated with a reduction in plasminogen activator inhibitor-1 (PAI-1) levels in L.s.-1.25-treated endothelial cells. Furthermore, only parent sulfated polysaccharides from L. saccharina (L.s.-P) and its fraction L.s.-1.25 were powerful inhibitors of basic fibroblast growth factor (bFGF) induced pathways. Consistently, the L.s.-1.25 fraction as well as L.s.-P successfully interfered with fibroblast binding to human bFGF. The incorporation of L.s.-P or L.s.-1.25, but not L.s.-1.0 into Matrigel plugs containing melanoma cells induced a significant reduction in hemoglobin content as well in the frequency of tumor-associated blood vessels. Moreover, i.p. administrations of L.s.-1.25, as well as L.s.-P, but not L.s.-1.0, resulted in a significant reduction of tumor growth when inoculated into syngeneic mice. Finally, L.s.-1.25 markedly inhibited breast cancer cell adhesion to human platelet-coated surfaces. Thus, sulfated fucans are mainly responsible for the anti-inflammatory, anticoagulant, antiangiogenic, and antitumor activities of sulfated polysaccharides from L. saccharina brown seaweed.

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Selective effects of L.s.-P and its fractions L.s.-1.0 and L.s.-1.25 on breast cancer cell adhesion to human platelets.(A) MDA-MB-231 breast cancer cells were pre-incubated with selected polysaccharide preparations prior to exposure to human platelet-coated plates. The images are representative of three independent experiments. (B) Quantitative analysis of cell adhesion was performed by counting the number of tumor cells adhered to at least three different fields. Results are expressed as mean percentage ± SEM of the treated samples versus control. *P<0.05; **P<0.01.
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pone-0017283-g006: Selective effects of L.s.-P and its fractions L.s.-1.0 and L.s.-1.25 on breast cancer cell adhesion to human platelets.(A) MDA-MB-231 breast cancer cells were pre-incubated with selected polysaccharide preparations prior to exposure to human platelet-coated plates. The images are representative of three independent experiments. (B) Quantitative analysis of cell adhesion was performed by counting the number of tumor cells adhered to at least three different fields. Results are expressed as mean percentage ± SEM of the treated samples versus control. *P<0.05; **P<0.01.

Mentions: We have recently demonstrated that the pool of sulfated polysaccharides from L. saccharina efficiently blocks the adhesion of a highly metastatic tumor cell line to human platelets [2], suggesting that this compound could also be a promising inhibitor of one of the earliest processes favouring tumor metastasis [22]. Here we examined the ability of L.s.-1.0 and L.s.-1.25 fractions to abrogate breast cancer cell adhesion to platelet-coated surfaces. Each preparation was added at a final concentration of 100 µg/ml to MDA-MB-231 breast cancer cell suspension before plating the cells, which were left to adhere to platelet-coated surfaces for 1 h. As shown in Figure 6A–B, the non-fractionated preparation L.s.-P inhibited tumor cell adhesion to platelets by 80%. Interestingly, both isolated fractions L.s.-1.0 and L.s.-1.25 significantly suppressed these heterotypic interactions, but L.s.-1.25 fraction was much more active than L.s.-1.0 (80%; P<0.003 reduction vs 30% reduction; P<0.05). These results demonstrate that the ability of L.s.-P to inhibit heterotypic cell adhesion between tumors and human platelets is mainly associates with the effect of the L.s.-1.25 fraction.


Fucans, but not fucomannoglucuronans, determine the biological activities of sulfated polysaccharides from Laminaria saccharina brown seaweed.

Croci DO, Cumashi A, Ushakova NA, Preobrazhenskaya ME, Piccoli A, Totani L, Ustyuzhanina NE, Bilan MI, Usov AI, Grachev AA, Morozevich GE, Berman AE, Sanderson CJ, Kelly M, Di Gregorio P, Rossi C, Tinari N, Iacobelli S, Rabinovich GA, Nifantiev NE, Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO), Ita - PLoS ONE (2011)

Selective effects of L.s.-P and its fractions L.s.-1.0 and L.s.-1.25 on breast cancer cell adhesion to human platelets.(A) MDA-MB-231 breast cancer cells were pre-incubated with selected polysaccharide preparations prior to exposure to human platelet-coated plates. The images are representative of three independent experiments. (B) Quantitative analysis of cell adhesion was performed by counting the number of tumor cells adhered to at least three different fields. Results are expressed as mean percentage ± SEM of the treated samples versus control. *P<0.05; **P<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3046160&req=5

pone-0017283-g006: Selective effects of L.s.-P and its fractions L.s.-1.0 and L.s.-1.25 on breast cancer cell adhesion to human platelets.(A) MDA-MB-231 breast cancer cells were pre-incubated with selected polysaccharide preparations prior to exposure to human platelet-coated plates. The images are representative of three independent experiments. (B) Quantitative analysis of cell adhesion was performed by counting the number of tumor cells adhered to at least three different fields. Results are expressed as mean percentage ± SEM of the treated samples versus control. *P<0.05; **P<0.01.
Mentions: We have recently demonstrated that the pool of sulfated polysaccharides from L. saccharina efficiently blocks the adhesion of a highly metastatic tumor cell line to human platelets [2], suggesting that this compound could also be a promising inhibitor of one of the earliest processes favouring tumor metastasis [22]. Here we examined the ability of L.s.-1.0 and L.s.-1.25 fractions to abrogate breast cancer cell adhesion to platelet-coated surfaces. Each preparation was added at a final concentration of 100 µg/ml to MDA-MB-231 breast cancer cell suspension before plating the cells, which were left to adhere to platelet-coated surfaces for 1 h. As shown in Figure 6A–B, the non-fractionated preparation L.s.-P inhibited tumor cell adhesion to platelets by 80%. Interestingly, both isolated fractions L.s.-1.0 and L.s.-1.25 significantly suppressed these heterotypic interactions, but L.s.-1.25 fraction was much more active than L.s.-1.0 (80%; P<0.003 reduction vs 30% reduction; P<0.05). These results demonstrate that the ability of L.s.-P to inhibit heterotypic cell adhesion between tumors and human platelets is mainly associates with the effect of the L.s.-1.25 fraction.

Bottom Line: This effect correlated with a reduction in plasminogen activator inhibitor-1 (PAI-1) levels in L.s.-1.25-treated endothelial cells.The incorporation of L.s.-P or L.s.-1.25, but not L.s.-1.0 into Matrigel plugs containing melanoma cells induced a significant reduction in hemoglobin content as well in the frequency of tumor-associated blood vessels.Moreover, i.p. administrations of L.s.-1.25, as well as L.s.-P, but not L.s.-1.0, resulted in a significant reduction of tumor growth when inoculated into syngeneic mice.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas y Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.

ABSTRACT
Sulfated polysaccharides from Laminaria saccharina (new name: Saccharina latissima) brown seaweed show promising activity for the treatment of inflammation, thrombosis, and cancer; yet the molecular mechanisms underlying these properties remain poorly understood. The aim of this work was to characterize, using in vitro and in vivo strategies, the anti-inflammatory, anti-coagulant, anti-angiogenic, and anti-tumor activities of two main sulfated polysaccharide fractions obtained from L. saccharina: a) L.s.-1.0 fraction mainly consisting of O-sulfated mannoglucuronofucans and b) L.s.-1.25 fraction mainly composed of sulfated fucans. Both fractions inhibited leukocyte recruitment in a model of inflammation in rats, although L.s.-1.25 appeared to be more active than L.s.-1.0. Also, these fractions inhibited neutrophil adhesion to platelets under flow. Only fraction L.s.-1.25, but not L.s.-1.0, displayed anticoagulant activity as measured by the activated partial thromboplastin time. Investigation of these fractions in angiogenesis settings revealed that only L.s.-1.25 strongly inhibited fetal bovine serum (FBS) induced in vitro tubulogenesis. This effect correlated with a reduction in plasminogen activator inhibitor-1 (PAI-1) levels in L.s.-1.25-treated endothelial cells. Furthermore, only parent sulfated polysaccharides from L. saccharina (L.s.-P) and its fraction L.s.-1.25 were powerful inhibitors of basic fibroblast growth factor (bFGF) induced pathways. Consistently, the L.s.-1.25 fraction as well as L.s.-P successfully interfered with fibroblast binding to human bFGF. The incorporation of L.s.-P or L.s.-1.25, but not L.s.-1.0 into Matrigel plugs containing melanoma cells induced a significant reduction in hemoglobin content as well in the frequency of tumor-associated blood vessels. Moreover, i.p. administrations of L.s.-1.25, as well as L.s.-P, but not L.s.-1.0, resulted in a significant reduction of tumor growth when inoculated into syngeneic mice. Finally, L.s.-1.25 markedly inhibited breast cancer cell adhesion to human platelet-coated surfaces. Thus, sulfated fucans are mainly responsible for the anti-inflammatory, anticoagulant, antiangiogenic, and antitumor activities of sulfated polysaccharides from L. saccharina brown seaweed.

Show MeSH
Related in: MedlinePlus