Fucans, sulfated polysaccharides extracted from brown seaweeds, inhibit vascular smooth muscle cell proliferation. II. Degradation and molecular weight effect.
Logeart D, Prigent-Richard S, Boisson-Vidal C, Chaubet F, Durand P, Jozefonvicz J, Letourneur D. LRM, CNRS URA 502, INFREMER URM2, University Paris XIII, France.
Fucan, a sulfated polysaccharide extracted from brown seaweeds, inhibits smooth muscle cell (SMC) proliferation with a higher antiproliferative activity than heparin (Logeart et al., Eur. J. Cell Biol. 74, 1997, this issue). In order to investigate the structure-activity relationship of fucan on SMC growth, we have prepared by size exclusion chromatography fucan fractions of various molecular masses ranging from 5.5 to 556 kDa. Our experiments showed that the antiproliferative activity is dependent on the molecular weight of the polysaccharide. The molecular weight threshold indicated that about 30 saccharidic units on fucan were necessary to give the antiproliferative activity on SMCs. A kinetics study of DNA synthesis using tritiated thymidine uptake was also performed with different molecular weight fucan fractions. Although all tested fractions acted as soon as the cells enter the first cell cycle, the duration and potency of action varied. Moreover, displacement experiments of iodinated fucan revealed that the low molecular fucan fraction interacted weakly with the binding sites. Finally, gel permeation chromatography of internalized radiolabeled heparin and fucans was performed with SMCs. A rapid degradation of internalized heparin was observed, whereas only low molecular weight fucan fractions were partially degraded by SMCs. Together, these results indicate the significance of molecular weight on the antiproliferative activity of fucans on SMCs, and might help to understand their mechanism of action. In addition, the degradation experiments with internalized heparin and fucans ruled out a direct link between polysaccharide degradation and the antiproliferative effect on SMCs.
PMID: 9438135, UI: 98101010


Laminarin sulfate mimics the effects of heparin on smooth muscle cell proliferation and basic fibroblast growth factor-receptor binding and mitogenic activity.
Miao HQ, Ishai-Michaeli R, Peretz T, Vlodavsky I
Department of Oncology, Hadassah University Hospital, Jerusalem, Israel.
Heparin and heparin-like molecules may function, apart from their effect on hemostasis, as regulators of cell growth and neovascularization. We investigated whether similar effects are exerted by laminarin sulfate, an unrelated polysulfated saccharide isolated from the cell wall of seaweed and composed of chemically O-sulfated beta-(1,3)-linked glucose residues. Laminarin sulfate exhibits about 30% of the anticoagulant activity of heparin and is effective therapeutically in the prevention and treatment of cerebrovascular diseases. We characterized the effect of laminarin sulfate on interaction of the heparin-binding angiogenic factor, basic fibroblast growth factor (bFGF), with a naturally produced subendothelial extra-cellular matrix (ECM) and with cell surface receptor sites. Laminarin sulfate (1-2 micrograms/ml) inhibited the binding of bFGF to ECM and to the surface of vascular smooth muscle cells (SMC) in a manner similar to that observed with heparin. Likewise, laminarin sulfate efficiently displaced both ECM- and cell-bound bFGF at concentrations as low as 1 microgram/ml. Both laminarin sulfate and heparin efficiently induced restoration of bFGF receptor binding in xylosyltransferase-deficient CHO cell mutants defective in initiation of glycosaminoglycan synthesis. Moreover, laminarin sulfate elicited bFGF receptor activation and mitogenic response in heparan sulfate (HS)-deficient, cytokine-dependent lymphoid cells. These results indicate that laminarin sulfate effectively replaced the need for heparin and HS in the induction of bFGF receptor binding and signaling. In other experiments, laminarin sulfate was found to inhibit the proliferation of vascular SMC in a manner similar to that observed with heparin. These effects of laminarin sulfate may have potential clinical applications in diverse situations such as wound healing, angiogenesis, and atherosclerosis.
PMID: 7650058, UI: 95378308


Arzneimittelforschung 1992 Aug;42(8):1005-8
Synthesis of laminarin sulfates with anticoagulant activity.
Alban S, Kraus J, Franz G
Department of Pharmacy, University of Regensburg, Fed. Rep. of Germany.
Laminarin sulfates were synthesized without significant degradation of the genuine laminarin chain using SO3/pyridine complex as a sulfation reagent. 6 derivatives with a degree of sulfation (d.s.) ranging from 0.30 to 2.26 could be obtained. According to methylation analysis the C-6-OH-groups of the glucose molecules were preferentially substituted, followed by the OH-groups at C-2 and C-4. The derivatives Lam S1 (d.s. = 0.30) and Lam S2 (d.s. = 0.64) showed no activity in the blood coagulation tests. With increasing d.s. the anticoagulant activity increased until an optimum d.s. of 1.49. Anticoagulant laminarin sulfates showed significant activity in the activated partial thromboplastin time (APTT) test but were less active in the anti-Factor Xa as well as anti-Factor IIa assay. Therefore, the anticoagulant activity of the synthesized laminarin sulfates is due to the interaction at an early stage of the coagulation cascade and neither to a direct inhibition of Factor Xa and IIa nor to an indirect effect mediated by antithrombin III.


Isolation, purification, and characterization of fucose-containing sulfated polysaccharides from the brown seaweed Ecklonia kurome and their blood-anticoagulant activities.
Nishino T, Yokoyama G, Dobashi K, Fujihara M, Nagumo T
Department of Biophysics, School of Hygienic Sciences, Kitasato University, Kanagawa, Japan.
A sulfated polysaccharide fraction, obtained from the hot-water extract of the brown seaweed, Ecklonia kurome by removing laminaran and the major part of alginic acid, gave sulfated polysaccharides (B-I, B-II, C-I, and C-II) by both anion-exchange chromatography on a column of Ecteola-cellulose and by fractional precipitation with ethanol containing 0.3% calcium acetate, and then by gel-filtration chromatography on a Sepharose 4B column. B-I and B-II are composed of fucose, galactose, mannose, xylose, glucuronic acid, and ester sulfate in the approximate molar ratios of 1.00:0.36:0.48:1.08:1.85:2.35 and 1.00:0.81:0.18:0.45:0.61:2.00, respectively. C-I and C-II are composed of fucose, galactose, glucuronic acid, and ester sulfate in approximate molar ratios of 1.00:0.03:0.03:1.61 and 1.00:0.19:0.07:1.48, respectively. Blood-anticoagulant activities with respect to activated partial thromboplastin time (APTT) were approximately 24, 19, 81, and 85% of that of heparin for B-I, B-II, C-I, and C-II, respectively. All the polysaccharides showed slight antithrombin activity. No antifactor Xa activity was observed for any of the polysaccharides.
PMID: 2720702, UI: 89249063


Thromb Res 1987 Jun 15;46(6):793-801
Inhibition of vascular smooth muscle cell proliferation in culture by pentosan polysulphate and related compounds.
Paul R, Herbert JM, Maffrand JP, Lansen J, Modat G, Pereillo JM, Gordon JL
Pentosan polysulphate (PPS; SP 54; Hemoclar), a highly sulphated semi-synthetic polysaccharide of MW 4.7 kD, was tested in vitro as an inhibitor of rabbit aortic smooth muscle cell (SMC) proliferation and its effects were compared with those of dextran sulphate, laminarin sulphate and heparin fractions. When added to the cell cultures simultaneously with foetal calf serum, all sulphated polysaccharides inhibited cell growth. PPS was five fold more active than heparin and its low molecular weight fractions. A high molecular weight fraction of PPS was the most active inhibitor (IC50: 2.7 micrograms/ml vs 45 micrograms/ml for PPS, and 241 micrograms/ml for heparin). When PPS and heparin were pre-incubated with the cells for three days, then removed before foetal calf serum was added to stimulate growth, their inhibitory effects were comparable with those seen when the compounds were present throughout the growth phase, suggesting that they exert their effect by binding to the cell surface, and not by interacting with the growth factors in serum.
PMID: 2442829, UI: 87320267


The alginates found in kelp/seaweeds have a soothing and cleansing effect on the digestive tract and are known to help prevent the absorption of toxic metals like mercury, cadmium, plutonium and cesium. (Tanaka Y, et al, Application of algal polysaccharides as in vivo binders of metal pollutant. Proc Seventh Int Seaweed Symp, 602-607, Wiley & Sons, 1972) Kelp is also therapeutic for heart disease, high cholesterol, and high blood pressure. (Kameda J, I Fukushima Igaku Zasshi, 11, 289,1961; Funayama S, et al, Planta Medica, 41, 29, 1981; Kosuge T, et al, Yakugaku Zasshi, 103(6), 683,1983)