Mar. Drugs 2013, 11(12), 4876-4901; doi:10.3390/md11124876

Review
Anticancer and Cancer Preventive Properties of Marine Polysaccharides: Some Results and Prospects
Sergey N. Fedorov , Svetlana P. Ermakova , Tatyana N. Zvyagintseva and Valentin A. Stonik *
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Science, Prospect 100 let Vladivostoku, 159, Vladivostok 690022, Russia; E-Mails: fedorov@piboc.dvo.ru (S.N.F.); swetlana_e@mail.ru (S.P.E.); zvyag@piboc.dvo.ru (T.N.Z.)
*
Author to whom correspondence should be addressed; E-Mail: stonik@piboc.dvo.ru; Tel.: +7-4232-311-168; Fax: +7-4232-314-050.
Received: 31 October 2013; in revised form: 21 November 2013 / Accepted: 22 November 2013 /
Published: 2 December 2013

Abstract

: Many marine-derived polysaccharides and their analogues have been reported as showing anticancer and cancer preventive properties. These compounds demonstrate interesting activities and special modes of action, differing from each other in both structure and toxicity profile. Herein, literature data concerning anticancer and cancer preventive marine polysaccharides are reviewed. The structural diversity, the biological activities, and the molecular mechanisms of their action are discussed.
Keywords:
marine organisms; polysaccharides; anticancer; chemoprevention; anticarcinogenic; mechanisms of action

1. Introduction

Polysaccharides are characteristic metabolites of many marine organisms, particularly of algae. Macrophytes such as brown, red, and green algae are known as traditional food ingredients for people populating seaboard geographic areas. In many countries, brown algae belonging to Laminaria, Saccharina, Fucus, Alaria, Sargassum, Undaria, Pelvetia genera, green algae such as Ulva spp., Caulerpa lentilifera as well as red algae such as Gracilaria spp., Porphyra spp. and others represent an important part of diet, while the purified gelling and thickening ingredients are predominant as food products of algal origin in European countries and the USA. Nowadays, algae have been marketed worldwide as constituents of dietary supplements due to their antimutagenic, anticoagulant, and antitumor properties as well as the high content of so-called dietary fiber.

High content of polysaccharides not only in algae, but also in many other marine organisms, their unusual structures and useful properties make these compounds promising natural products for medicinal and dietary applications, and are utilized in various biotechnologies [1]. Polysaccharides are used in drug compositions, burn dressings, as materials for encapsulation, in various drinks, etc. The therapeutic potential of marine polysaccharides enables their utilization for cell therapy and tissue engineering [2].

Many polysaccharides and/or their derivatives such as degraded and semi-synthetic products, obtained by chemical modifications, demonstrate anticancer and cancer preventive properties. They can possess either a direct inhibitory action on cancer cells and tumors or influence different stages of carcinogenesis and tumor development, recover the broken balance between proliferation and programmed cell death (apoptosis) and are useful for cancer prophylactics. Some of these marine natural products have advantages due to their availability, low toxicity, suitability for oral application as well as having a great variety of mechanisms of action [3]. The methods of extraction, fractionation, and purification of polysaccharides from various sources are well known and have been published in many articles [4,5,6,7,8].

Herein, we review some of the literature data concerning anticancer and cancer preventive activity of marine polysaccharides with particular attention to results of the last 10 years.

2. Polysaccharides from Brown Algae

2.1. Fucoidans

Polysaccharides from brown algae (Phaeophyceae) are well known for their anticancer and cancer preventive properties [9]. These compounds have various important biological functions including a protective role against heavy metal toxicity [10].

Fucoidans can be roughly divided into structural types as follows: α-l-fucans, galactofucans, fucomannouronans and other intermediate structures [11]. Fucoidans isolated from many edible brown algae contain mainly sulfated l-fucose residues attached to each other by α-1,3- or interchangeable α-1,3- and α-1,4-bonds. The regular structures may be masked by random acetylation and sulfation. Some fucoidans have branched structures. As a rule, fucoidans from different algal species differ from each other and vary not only in positions and level of sulfation and molecular mass, but sometimes in the structures of the main carbohydrate chains [12,13]. For example, the fucoidan from the brown alga Saccharina (=Laminaria) cichorioides is 2,4-disulfated 1,3-α-l-fucan (Figure 1), while the fucoidan from Fucus evanescens (Figure 2) contains blocks of α-1,3-fucooligosaccharides and α-1,4-fucooligosaccharides sulfated at the position 2 in fucose residues [14,15,16,17].

Marinedrugs 11 04876 g001 200
Figure 1. Fucoidan from Laminaria cichorioides.

Click here to enlarge figure

Figure 1. Fucoidan from Laminaria cichorioides.
Marinedrugs 11 04876 g001 1024
Marinedrugs 11 04876 g002 200
Figure 2. Fucoidan from F. evanescens.

Click here to enlarge figure

Figure 2. Fucoidan from F. evanescens.
Marinedrugs 11 04876 g002 1024

Galactofucans in contradistinction from α-l-fucans demonstrate considerable structural diversity [18,19]. Sulfated and often acetylated galactofuсans are also widespread in brown algae, including edible ones, such as Undaria pinnatifida and Laminaria japonica. The main chain of galactofucan can be constructed of blocks or of alternating residues of fucose and galactose. The type of bonds between the monosaccharide residues in galactofuсans, the structure of branchings, the position of sulfates or acetates, as well as the molecular weight can be very multifarious [13,20]. For example the structural fragment of galactofucan from L. japonica [21] is provided in Figure 3.

Marinedrugs 11 04876 g003 200
Figure 3. Galactofucan from L. japonica.

Click here to enlarge figure

Figure 3. Galactofucan from L. japonica.
Marinedrugs 11 04876 g003 1024

Some brown algae species contain other fucose-embracing heteropolysaccharides such as rhamnofucanes, uronofucanes, etc. For example, the main structure of the fucoglucuronomannan from Kjellmaniella crassifolia is [-4-d-GlcpUAβ1-2(l-Fucp(3-O-sulfate)α1-3)d-Manpα1-]n [22]. Uronofucanes are often named as U-fucoidans.

The structural diversity of fucoidans has not yet been sufficiently studied. The structural complexity of fucoidans, the existence of many sub-classes of these glycans in their biological sources as well as a lack of automatic sequencing methods for these polysaccharides have stimulated structure-function studies on the so-called fucanomes in the corresponding marine organisms [23,24]. This research is necessary for the solution of problems of standardization of preparations on the basis of fucoidans, which have attracted attention as practically nontoxic natural products [25,26,27] with antitumor, immunomodulatory, and other useful properties [24,28,29,30].

The anticancer properties of fucoidans have been established many times by in vitro and in vivo experiments [9,12,13,31,32,33]. It was reported that Cladosiphon fucoidan prevented the attachment of Helicobacter pylori to the mucin of the gastric tract and, therefore, reduced the risk of associated gastric cancer [34]. While using AGS human gastric adenocarcinoma cells and fucoidan from Fucus vesiculosus, it was established that treatment with fucoidan resulted not only in apoptosis of these cells, but also in autophagy with the formation of autophagosomes in fucoidan-treated cells, the conversion of microtubule-associated protein light chain 3 to light chain 3-II and the increase of beclin-1 level [35]. Several reports have also suggested cancer preventive effects of fucoidans on different cellular models. Galactofucan from U. pinnatifida inhibited proliferation of prostate cancer PC-3, cervical cancer HeLa, alveolar carcinoma A549, and hepatocellular carcinoma HepG2 cells in a similar pattern to the commercial fucoidan from F. vesiculosus [20]. Fucose-containing sulfated polysaccharides from brown algae Sargassum henslowianum and F. vesiculosus decreased the proliferation of melanoma B16 cells in a dose-response manner. Flow cytometric analysis by Annexin V staining established that both preparations influenced the translocation of membrane phospholipids and activated caspase-3 followed by apoptosis of tumor cells in in vitro experiments [36]. Fucoidan from Ascophyllum nodosum induced the activation of caspases-9 and -3 and the cleavage of PARP led to apoptotic morphological changes and altered the mitochondrial membrane permeability [37]. Sulfated polysaccharide isolated from the enzymatic digest of Ecklonia cava had an effect on caspases-7 and -8 and controlled the cellular membrane molecules Bax and Bcl-xL [38]. The fucoidan from Sargassum filipendula showed antiproliferative activity on HeLa cells [39] and induced apoptosis by mitochondrial release of apoptosis inducing factor (AIF) into cytosol, but was not able to activate caspases [40]. The caspase-independent apoptotic pathway was demonstrated for fucoidan from Cladosiphon novae-caledoniae [41]. The differences in the mechanisms of apoptosis probably depend upon the structural characteristics of fucoidans and the type of cell lines. Fucoidans were shown to induce apoptosis of some other cancer cells, for example HT-29, HCT116, and HCT-15 human colon cancer cells [42,43] as well as MCF-7 (breast adenocarcinoma) [44], melanoma SK-Mel-28, breast cancer T-47D [45], and human promyeloid leukemic cell lines [46]. MAPK pathways are involved in cellular proliferation, differentiation, and apoptosis induced by fucoidans. The fucoidan from F. vesiculosus clearly decreased the phosphorylation of ERKs but not p38 [47]. Another group reported that the pro-apoptotic effect of fucoidan from F. vesiculosus was mediated by the activation of ERKs, p38 and by the blocking of PI3K/Akt signaling pathway in HCT-15 cells [42].

Angiogenesis is a multistep process whereby the new blood vessels develop from the pre-existing vasculature. It involves migration, proliferation and differentiation of mature endothelial cells, and is regulated by interactions of endothelial cells with angiogenesis-inducing factors and extracellular matrix components [48]. Fucoidans may suppress tumor growth by inhibiting tumor-induced angiogenesis. Natural and oversulfated fucoidans suppressed the VEGF165 induced proliferation and the migration of human umbilical vein endothelial cells (HUVEC) by preventing the binding of VEGF165 to its cell surface receptor and inhibiting the VEGF-mediated signaling transduction [49]. In addition, the growth of two types of murine tumor cells inoculated into the footpads of mice was suppressed by administration of natural and oversulfated fucoidans. The relationship between sulfate content in fucoidan from U. pinnatifida and the proliferation of human stomach cancer cell line AGS was published [50]. These data showed that antiangiogenic and antitumor activity of fucoidans can be potentiated by increasing the sulfate groups in the molecule [51]. The relationship between the sulfate content of fucoidan and its inhibitory effect on the proliferation of U937 cells was also reported [52]. These results indicated that oversulfated fucoidan induced apoptosis through caspase-3 and -7 activation. The effect of the molecular weight of fucoidan from U. pinnatifida on the inhibition of cancer cell growth has been investigated. The anticancer activity of fucoidans could be increased by lowering their molecular weight whereby they are depolymerized by mild hydrolysis without a considerable amount of desulfation [53]. The mechanism by which fucoidans inhibited the invasion/angiogenesis of tumor cells has not been clearly elucidated. VEGF is a known angiogenic factor. Fucoidan from C. novae-caledonia kylin digested with the abalone glycosidase was responsible for the reduction of MMP-2/9 activities and the decrease in VEGF expression with subsequent inhibition of invasion and suppression of tubules formation in tumor cells [54].

Fucoidans are able to inhibit metastasis of cancer cells. Cell surface receptors belonging to the integrin family have been demonstrated to be involved in the invasion and the metastasis of tumors. The fucoidan from A. nodosum inhibited adhesion of MDA-MB-231 (breast adenocarcinoma) cells to fibronectin by binding it and modulating the reorganization of the integrin 5 subunit and down-regulating the expression of vinculin [55].

Cancer preventive properties of fucoidans have been shown in many experiments. For example, decrease of clonogenic growth of tumor cells was demonstrated after treatment with fucoidans [30,45,56]. The inhibition of cell transformation provided evidence on the anti-tumorigenic potential of fucoidans from A. nodosum [57], S. japonica, U. pinnatifida, Alaria sp., and F. evanescens [29,45,58].

Fucoidans may enhance the anticancer action of some low molecular weight compounds. For example, the fucoidan from the Far-eastern brown seaweed F. evanescens at a concentration of 500 μg/mL was not cytotoxic in human malignant lymphoid MT-4 or Namalwa cells. Pretreatment of MT-4, but not Namalwa cells with fucoidan followed by the exposure to DNA topoisomerase II inhibitor etoposide led to about a two-fold increase in the relative apoptotic index as compared with etoposide itself [56]. The fucoidan from S. cichorioides enhanced the antiproliferative activity of resveratrol at nontoxic doses and facilitated the resveratrol-induced apoptosis in the HCT116 cell line. Furthermore, the cells were sensitized by the fucoidan to the action of resveratrol and the inhibition of HCT116 clonogenic capacity was indicated [59].

Some fucoidans showed cytoprotective properties. It is important that fucoidan may be useful for the recovery of 5-fluorouracil (5-FU)-treated antigen-presenting dendritic cells, because this clinical anticancer agent induces immunosuppression in cancer patients as a side effect [60].

In the majority of cases, molecular mechanisms of anticancer and cancer preventive actions of fucoidans were established by in vitro studies. Many fucoidans induced apoptosis of tumor cells through activation of the caspases and by enhancing mitochondrial membrane permeability. Sometimes this mechanism involved the reactive oxygen species (ROS)-dependent JNK activation as was shown for partly digested fucoidan from commercially available seaweed C. novae-caledoniae using MCF-7 and MDA-MB-10A tumor cells [41].

Fucoidans modulate the immune system and may induce functional maturation of human monocyte-derived dendritic cells (DC) [61]. Ligand scavenger receptor class A (SR-A) indirectly participates in maturation of human blood dendritic cells via production of tumor necrosis factor followed by stimulation of T-cells. Thereby, fucoidan acts as a scavenger receptor agonist and maturation is eliminated by pretreatment with TNF-neutralizing antibodies [62]. At a later date, it was confirmed that SR-A plays a crucial role in affecting the DC-mediated presentation of cancer antigens to T cells in human cancer cells, and it was also established that fucoidan promoted the DCs maturation. The fucoidan-treated DCs stimulated the CD8+ T limphocytes to release more interferon-γ than non-fucoidan-treated cells. It was found that fucoidan enhanced the cross-presentation of NY-ESO-1 cancer testis antigen to T cells and it led to the increase of T-cell cytotoxicity against NY-ESO-1 human cancer cells [63]. Cytotoxic activities of natural killer cells were also activated in vivo after administration of fucoidans from Sargassum sp. and F. vesiculosus to mice [36].

Fucoidan from F. vesiculosus inhibited the migration and the invasion of human lung cancer cells decreasing the cytosolic and nuclear levels of kappa-B nuclear factor [64]. Treatment of mouse breast cancer cells with fucoidan showed that the enhanced antitumor activity was associated with decreased angiogenesis via the down-regulation of vascular endothelial growth factor and increased induction of apoptosis [65].

It has been suggested that the anticarcinogenic action of fucoidan from S. cichorioides is connected with its ability to interact directly with epidermal growth factor (EGF) and prevents its binding to EGF receptor (EGFR). Actually, in experiments with neoplastic transformation of JB6 mouse epidermal cells induced by EGF or 12-O-tetradecanoylphorbol-13 acetate, a Russian-Korean group of scientists reported that inhibition of EGFR phosphorylation was followed by inhibition of the activities of some extracellular signal regulated kinases that resulted in the inhibition of AP-1 nuclear factor transactivation [66,67].

Ultraviolet irradiation is known to induce skin aging and cause skin cancer. UVB stimulates the activation of cellular signaling transduction followed by the production of metalloproteinases (MMPs). Fucoidans suppressed the UVB induced MMP-1 expression and inhibited ERKs activity in human skin fibroblasts in a dose-dependent manner. They inhibited significantly MMP-1 promoter activity and increased type I procollagen mRNA and protein expression. It was concluded that Costaria costata fucoidan may be considered as a potential agent for the prevention and treatment of skin photoaging [68,69,70]. The fucoidan from F. vesiculosus post-translationally regulated MMP-9 secretion from human monocyte cell line U937 [71].

Thus, the molecular mechanisms of anticancer and cancer preventive actions of fucoidans are rather complicated and may include inhibitory effects against cancer cell proliferation and induction of tumor cells apoptosis. In addition, these polysaccharides stimulate immunity and inhibit angiogenesis. The cancer preventive action of fucoidans includes such useful properties as anti-inflammatory, anti-adhesive [72], antioxidant and antiviral effects [73,74,75,76] as well as their capability to bind heavy metals. Moreover, these compounds may delay and decrease the action of such factors of carcinogenesis as some tumor promoters (EGF, phorbol esters), defend against UV radiation and inhibit the tumor invasion by modulation of metalloproteinases. Possibly, these effects depend on the differences in the structures of fucoidans isolated from various biological sources and on their physico-chemical characteristics such as molecular weight.

Daily consumption of fucoidan-containing algae was proposed as a factor in the lowering of postmenopausal breast cancer incidence and mortality. Urinary human urokinase-type plasminogen activator receptor concentration is higher among postmenopausal women breast cancer patients. It was shown that this concentration was decreased by about 50% after seaweed supplementation [77]. In addition, fucoidans reduced the toxicity of chemotherapy for patients with unresectable advanced or recurrent colorectal cancer. Fucoidan may enable the continuous administration of such drugs as oxaliplatin plus 5FU/leucovorin and, as a result, may prolong the survival of patients [78]. In some countries food supplements and drinks containing fucoidans are used to treat patients having different cancers. In many countries fucoidan-containing extracts are used as a remedy in traditional medicine.

In our opinion, the perspectives of studies on fucoidans are connected with further search for new structural variants of these types of polysaccharides and the relationships established between the structures and the biological activities. The great diversity of fucoidans, presenting in brown algae and covering a much broader range than only those having a fucan backbone, provides potential for the future discovery of numerous new polysaccharides of this class and their derivatives. Fucoidan bioactivities depend on the extraction and the purification methods used, because fucoidans obtained from the same biological source using different methods differ from each other in the content of sulfate groups and in the impurities [79]. Furthermore it is known that the content and structure of fucoidans depends on the seaweed species, the parts of the plant, the harvest season and mainly on the stage of development of the algae [58,80,81].

The recent rapid progress in studies on fucoidans has been achieved by application of modern methods of structural investigation such as 2D NMR, MALDI-TOF and tandem ESI mass-spectrometry [82,83] as well as new techniques of molecular biology and pharmacology such as fluorescent staining, flow cytometry, mi-RNA, Western blot, etc.

2.2. Laminarans

Important results have been obtained in the studies on other algal polysaccharides from brown algae laminarans, as potential cancer preventive agents. Laminarans are low molecular weight polysaccharides (MW about 3–6 kDa) consisting mainly of 1,3-linked β-d-glucopyranose residues with a small number of 1,6-bonded β-d-glucopyranose units in the main and the branching chains. Their carbohydrate chains are terminated with d-mannitol residues (so-called M-chains) or contain glucopyranose residues only (so-called G-chains) (Figure 4). Sometimes terminal residues of M-chains may be additionally glycosylated or M-chains may be completely absent [84]. Branching at positions 2 and 6 was found in the laminaran from Saccharina longicrucis [85].

Marinedrugs 11 04876 g004 200
Figure 4. The structures of G- and M-chains of laminarans.

Click here to enlarge figure

Figure 4. The structures of G- and M-chains of laminarans.
Marinedrugs 11 04876 g004 1024

High molecular weight laminaran (19–27 kDa) was recently isolated from the brown seaweed Eisenia bicyclis. It was shown that this 1,3;1,6-β-d-glucan contained 1,6-linked glucose residues in both branches and the main chain, basically in the non-reduced ends of the molecules. This laminaran and its products of enzymatic degradation inhibited the colony formation of SK-Mel-28 and colon cancer DLD cells. The increase of the content of 1,6-linked glucose residues and the decrease of the molecular weight improved the anticancer effect in this series of substances [85]. It is known that algal glucans suppress angiogenesis in tumor growth. Recent findings show that they enhanced the tumor response to photodynamic therapy in C57BL/6 mice, administered subcutaneously with Lewis lung carcinoma cells. Ten days after implantation, the mice were treated with sodium porfimer, 24 h prior to laser irradiation with or without oral administration of β-d-glucans. When algal β-d-glucan was used, significantly reduced tumor growth was indicated [86].

Laminarans noticeably inhibited the formation of putrefactive and harmful compounds, such as indoles, p-cresol, ammonia, phenol, and sulfide, produced by the fecal microflora. These putrefactive compounds in rats fed low molecular alginate also tended to be lower. In both experiments (with laminaran and with alginic acid) the intestinal bacterial flora of rats was changed. Polysaccharides were fermented into propionic and butyric acids by intestinal microbiota, similar to the effects of prebiotics. These results suggest that the fermentation of laminaran by intestinal bacteria could suppress the risk of colorectal cancer [87,88]. It is of special interest that not only laminarans, but also other β-d-glucans, isolated from yeast, fungi and cereals demonstrated anti-cytotoxic, anti-mutagenic, and anti-tumorigenic properties, making this class of polysaccharides a promising promoter of health [89].

Tumor metastasis is connected with expression of heparanase, an endo-β-d-glucuronidase that degrades the main polysaccharide constituent of the extracellular matrix and the basement membrane. In fact, expression of the heparanase gene is associated with the invasive potential of tumors. Laminaran sulfate inhibited heparanase enzymatic activity and reduced the incidence of metastasis in experimental animals [90].

2.3. Alginic Acids

Alginic acids are widely distributed in the cell walls of brown seaweeds. These anionic polysaccharides were proved to be linear polymers containing blocks of 1,4-linked β-d-polymannouronate and α-l-polyguluronate (so-called M- and G-blocks) (Figure 5). Molecular masses of alginic acids ranged between 10 kDa and 600 kDa. These polysaccharides are used in the pharmaceutical industry and in biotechnology, particularly for cell immobilization and encapsulation.

Marinedrugs 11 04876 g005 200
Figure 5. Structure of alginic acid.

Click here to enlarge figure

Figure 5. Structure of alginic acid.
Marinedrugs 11 04876 g005 1024

Alginic acid-coated chitosan nanoparticles have been constructed as an oral delivery carrier for the legumain-based DNA vaccine. It was shown that this vaccine could effectively improve autoimmune response and protect against breast cancer in mice [91].

Biopreparations containing alginic acids probably have some cancer preventive properties because of the ability of polysaccharides to bind toxins and heavy metals in the intestines and transform these dangerous compounds into less harmful forms.

3. Polysaccharides from Red Algae

Red algae (Rhodophyta) contain several classes of well known polysaccharides, having wide application in microbiology, biotechnology and other fields, mainly due to the ability of their aqueous solutions to form strong gels. Sulfated galactans such as agar, agarose and carrageenans usually contain repeating disaccharides of β-(1→3)-linked and α-(1→4)-linked galactopyranosyl (Galp) residues. Several red algae species contain other polysaccharides, for example mannans and xylans [92].

All carrageenans consist of either galactose or galactose and 3,6-anhydrogalactose monosaccharide units and differ from each other in monosaccharide composition, level of sulfation, positions of sulfate groups and molecular weights. Three groups of carrageenans, so-called kappa-, iota- and lambda-carrageenans, are of commercial significance (Figure 6). Hybrid forms of carrageenans are also known.

Marinedrugs 11 04876 g006 200
Figure 6. Structures of repeating units of some carrageenans.

Click here to enlarge figure

Figure 6. Structures of repeating units of some carrageenans.
Marinedrugs 11 04876 g006 1024

Some representatives of this polysaccharide class demonstrate properties connected with cancer prevention, mainly due to antiviral, antioxidant properties, and stimulation of antitumor immunity. As is known, certain sexually transmitted human papillomavirus types are associated with the development of cervical cancer. Recently, it was established that carrageenan in nanomolar concentrations inhibits papillomavirus. However, clinical trials are needed to determine, whether carrageenans are effective as antiviral drugs against genital human papilloma viral infection or not [93].

κ-Carrageenans degraded by an oxidative method involving hydrogen peroxide (H2O2) treatment were evaluated as scavengers of superoxide anions and hydroxyl radicals by application of flow injection chemiluminescence technology. The values of IC50 of degraded κ-carrageenans labeled A, B, C, and D against the superoxide anion showed a positive correlation with molecular weight. As for hydroxyl radical scavenging, the EC50 values of degraded κ-carrageenans A, B, C, and D showed the same correlation. Therefore, these results indicated that κ-carrageenans with lower molecular weights have better antioxidant properties and may be promising for cancer prevention [94]. Carrageenan oligosaccharides from the red alga Kappaphycus striatum were perorally administrated during 14 days into mice inoculated with S180 tumor cell suspension. This resulted in growth inhibition of transplantable sarcoma cells, increased macrophage phagocytosis, enhanced antibody production, increased lymphocyte proliferation, stronger NK cell activity, and elevated levels of IL-2 and TNF-α. These results suggested that the studied oligosaccharides exert their antitumor effects by promoting the immune system [95]. In vivo antitumor activities for κ-carrageenan oligosachharides and low molecular λ-carrageenan from Chondrus ocellatus have been established. The latter also potentiated the antitumor effect of 5-FU [96,97]. Similar data were obtained in studies of sulfated polysaccharide from the red alga Champia feldmannii [98]. Thus, low molecular carrageenans and carrageenan oligosaccharides seem to be more promising cancer preventive agents than high molecular natural products belonging to this class of polysaccharides.

However, harmful gastrointestinal effects of both native and degraded carrageenans followed by the induction of neoplasms in animal experiments were reported [99]. Later, it was confirmed that degraded carrageenan induces colitis in rats in vivo and induces inflammation. However, in experiments in vitro, the preparation inhibited proliferation of THP-1 cells and arrested the cells in the G1 phase [100]. In another review concerning the toxicological effects of carrageenan on the gastrointestinal tract, it was demonstrated that systematically perorally administrated carrageenan was not carcinogenic. It was noted that previous toxicological studies involved administration of doses that exceeded those to which humans are exposed by several magnitudes [101]. Similar conclusion about the safety of peroral application of κ-carrageenan was made as a result of a 90-day dietary study in rats [102].

Thus, further investigations are needed to determine the applicability of partly degraded carrageenans as cancer preventive agents.

4. Polysaccharides from Green Algae

Among marine macrophytes, marine green algae have been less studied in comparison to brown and red algae as sources of polysaccharides with anticancer and cancer preventive properties. However, their antitumor properties have been sometimes reported, mainly for the polysaccharides belonging to the so-called ulvans. Ulvans, water soluble sulfated polysaccharides from the cell walls of green algae are characteristic of the plants, belonging to the genera Ulva, Enteromorpha, Monostroma, Caulerpa, Codium, and some others. They are composed of repeating disaccharide moieties, containing sulfated rhamnose and uronic acid (glucuronic or iduronic). The structure of the disaccharide moieties of ulvans resembles that of glycosaminoglycans, which occur in the extracellular matrix of connective tissues of animals. Some ulvans include also xylose residues (Figure 7) [103].

Marinedrugs 11 04876 g007 200
Figure 7. Structure of the main repeating disaccharide in Ulva rigida.

Click here to enlarge figure

Figure 7. Structure of the main repeating disaccharide in Ulva rigida.
Marinedrugs 11 04876 g007 1024

The highly pyruvated 1,3-β-d-galactan sulfate from the Pacific Codium yezoense and the similar polysaccharide from Codium isthmocladium represent another type of polysaccharides found in green algae [104,105]. Sulfated β-d-mannans like that isolated from Codium vermilara [106] have also been found.

Promising antioxidant and antiproliferative activities were recently found in the sulfated polysaccharides isolated from several tropical species of green algae. HeLa cell proliferation was inhibited between 36.3% and 58.4% after 72 h incubation with the polysaccharide isolated from Caulerpa prolifera [107]. Two polysaccharide fractions obtained from the green alga Caulerpa racemosa showed antitumor activities, and their inhibition rates of H22 tumor transplanted in mice were 59.5%–83.8% (48 h) and 53.9% (14 days) at a dose of 100 mg/kg/day, respectively [108].

In vivo and in vitro stimulation of immunity was indicated as the action of water-soluble sulfated polysaccharide fractions from Enteromorpha prolifera. These polysaccharides significantly increased ConA-induced splenocyte proliferation and induced the production of various cytokines via up-regulated m-RNA expression [109]. The ulvan from Ulva rigida induced more than a two times increase in the expression of some cytokines, stimulated the secretion and activity of murine macophages as well as inducing an increase in COX-2 and NOS-2 expression [110]. Ulvans from Ulva pertusa had little cytotoxicity against tumor cells, but significantly stimulated immunity, inducing considerable amounts of nitric oxide and cytokine production [111]. There are several reports concerning the antioxidant activities of ulvans in experimental D-galactosamine-induced hepatitis in rats [112,113].

The strong immuno-modulatory potencies as well as the antioxidant properties of polysaccharides from green algae suggest their potential cancer preventive activity and their future utilization as experimental immuno-stimulants.

5. Polysaccharides from Microalgae

There is little information concerning cancer preventive and anticarcinogenic properties of polysaccharides from marine microalgae, although these organisms have been used for a long time as food for humans, particularly Arthrospira (the former name Spirulina) and Porphyridium. Similar marine organisms belong to the classes Bacillariophyceae (diatoms), Cyanophyceae (blue-green algae), Porphyridiophyceae and partly to Chlorophyceae and Rhodophyceae. However, after the nuclear accident of Fukushima and the resulting radioactive pollution, the ability of marine algae to bio-accumulate radionuclides, has become a major concern. For example, the newly discovered green microalga, Parachlorella sp. binos (Binos) exhibited highly efficient incorporation of radioactive isotopes of iodine, strontium and cesium. The authors also showed the ability of microalgae to accumulate radioactive nuclides from water and soil samples collected from the heavily contaminated area in Fukushima [114]. Determination of the potential radioactive contamination of seaweeds is therefore crucial before further search for bioactive compounds. Polysaccharides isolated from various microalgae ranging from diatoms to green-blue algae demonstrated different activities, although direct anticancer properties were rarely reported [91]. Apoptogenic properties of red microalgal polysaccharides in two human tumor cell lines MCF-7 and HeLa were established [115]. Some microalgal polysaccharides were found to show antiviral activities against retroviruses. These viruses, containing reverse transcriptase are implicated in various types of leukemias and other tumors. Polysaccharides from the fresh water red microalga Porphyridium sp. were more active than those from Porphyridium aerogineum and Rhodella reticulata against murine leukemia virus (MULV) and murine sarcoma virus (MuSV-124) in cell culture [116]. Marine red microalgae polysaccharides and polysaccharides from other microalgae were also studied in this respect. For example, sulfated polysaccharides from the marine microalga Cochlodinium polykrikoides showed a significant in vitro antiviral activity against human immunodeficiency virus and absence of a cytotoxic effect directed against the host cells [117]. Antiviral properties were found in several other polysaccharides, isolated from different microalgae [118,119].

In addition, blue green algal polysaccharides were immuno-active and showed antioxidant and free radical scavenging properties [115]. High molecular weight polysaccharides from the fresh water Spirulina platensis and related species [120] were between one hundred and one thousand times more immuno-active than polysaccharide preparations from other biological sources that are used clinically for cancer immunotherapy. Actually, related compounds with similar properties should be found in the corresponding marine species. Antioxidant activity was also reported for polysaccharides from Porphiridium cruentum [121].

All these activities are usually associated with anticancer and cancer preventive properties. For example, it is known that oxidative stress can lead to cancer and some antioxidant marine products proved to be chemopreventive antitumor agents [122]. Cancer preventive action of the oligosaccharide derived from the microalga P. cruentum was reported [123]. Another example concerns the extract from the deep-sea water Spirulina maxima, which effectively suppressed the expression of Bcl2 in A549 cells and inhibited viability of other human cancer cells [124]. Spirulina platensis preparations showed the chemopreventive effect against carcinogenesis induced by dibutyl nitrosamine with the decrease of the incidence of liver tumors from 80% to 20%. However, it is unknown, whether polysaccharide contribution is significant in this case or not [125].

6. Polysaccharides from Marine Bacteria and Fungi

A great diversity of polysaccharides from marine bacteria and fungi also attract attention because of their structures, anticancer and cancer preventive properties. Polysaccharide B1 from the marine Pseudomonas sp. has repeating units as -2)-β-d-Galp(4-sulfate)(1,4)[β-d-Glcp(1,6)]-β-d-Galp(3-sulfate)(1- and demonstrated cytotoxicity against tumor cells, being more active to the central nervous system and lung cancer cell lines. It induced apoptosis in U937 cells [126].

The marine filamentous fungus Keissleriella sp. YS 4108 polysaccharide with a mean molecular weight of 130,000 Da showed radical eliminating and antioxidant actions in various in vitro systems. In addition to scavenging activities, the polysaccharide effectively blocked the non site-specific DNA strand-break induced by the Fenton reaction at concentrations of 0.1 and 1 mg/mL. These results suggested that this preparation could be of preventive and therapeutic significance to some life-threatening health problems such as cancer [127].

7. Polysaccharides from Marine Animals

Polysaccharides can be found in various marine animals such as sea cucumbers, sea urchins, sponges, starfish, ascidians, etc. They contain a great variety of polysaccharide compounds, including glycosaminoglycans, fucans, and galactans [23,128,129,130]. These compounds demonstrate diverse biological properties, including anticoagulant and antitrombotic [131,132,133], antioxidative [134], neuroprotective [135,136], and antiviral activity as well [8,137]. However, anticancer and cancer preventive activities of the polysaccharides from marine animals have been studied insufficiently. Polysaccharide SEP isolated from the eggs of the sea urchin Strongylocentrotus nudus effectively inhibited the growth of S180 tumor and the hepatocellular carcinoma in vivo via the activation of lymphocytes and macrophages, amplification of B and T cell proliferation, and increased secretion of such cytokines as IL-2, TNF-α and IFN-γ [138,139,140,141]. The sulfated polysaccharide conjugate from viscera of abalone Heliotis discus hannai, administered at doses of 1–40 mg/kg to mice inhibited tumor growth and increased lymphocyte proliferation, as well as natural killer cell activity and antibody production. A significant increase of immune function was observed in cyclophosphamide-induced immunosuppressive mice on administration of 40 mg/kg dose [142].

Cancer chemoprevention implies the use of natural or synthetic compounds for prevention, suppression or reversal of the process of carcinogenesis [143]. Cancer preventive compounds may stimulate anticancer immunity, inhibit inflammation, angiogenesis and tumor invasion, or protect from UV-radiation damage [144,145,146,147]. Preincubation with mytilan, a polysaccharide isolated from the mussel Crenomytilus grayanus, was followed by a normalization of the activity indicators of human peripheral blood lymphocytes and by a reduction of the number of morphological defects of the marine invertebrates larvae after UV-irradiation [148]. Sulfated polysaccharide obtained from the sea cucumber Cucumaria frondosa affected the maturation of monocyte-derived dendritic cells and their activation of allogeneic CD4(+) T cells in vitro by down regulation of the secretion of IL-10 and IL-12p40 at 100 μg/mL [149]. Some polysaccharides from the marine animals inhibited the binding of pro-inflammatory molecules, P- and L-selectins, to immobilized carbohydrate determinant sialyl Lewisx which is a component of cell surface glycoproteins presented in leukocytes and overexpressed in several tumor cells. As a consequence of their antiselectin activity, these polysaccharides attenuated metastasis and inflammation [150,151,152]. Oral administration (100 mg/kg body weight) for five days of sea cucumber fucoidan (SC-FUC) extracted from Acaudina molpadioides can significantly prevent the formation of gastric ulcer in rats. Moreover, SC-FUC pretreatment could alleviate ethanol-induced histological damage, reverse changes in tissue oxidation and antioxidase activities, and regulate the signaling pathways of mitogen-activated protein kinases and matrix metalloproteinases [153]. Chondroitin sulfate isolated from ascidian Styela clava inhibited phorbol ester- and TNF-α-induced expression of inflammatory factors VCAM-1, COX-2 and iNOS by blocking Akt/NF-κB activation in mouse skin [154,155]. Anti-inflammatory activity of heparin analogues from ascidians and marine shrimps was also reported [156,157]. The heparin isolated from white leg shrimp demonstrated anti-angiogenic activity [158].

8. Conclusion

To date, numerous polysaccharides have been isolated from different marine organisms ranging from marine bacteria to marine animals and several dozen of them have attracted attention as promising anticancer and cancer preventive substances. Some of these compounds are already used in clinical practice. Polysaccharide anticancer and cancer preventive substances demonstrate a wide variety of useful properties and mechanisms of action, including inhibition of tumor cell proliferation, induction of apoptosis, inhibition of angiogenesis, etc. These biopolymers and their derivatives frequently show radical scavenging, antiviral, and immuno-stimulatory properties. Polysaccharides obtained from marine invertebrates possess unique physico-chemical and biological properties, which justify intensive research efforts in the future. The increasing exploration of marine biological sources will help to identify the most promising of these compounds.

Acknowledgments

The study was supported by the Program of the Presidium of RAS “Molecular and Cell Biology” (grant 12-IP6-11), Grant No. 13-03-00986 from the RFBR, and Grant of President of Russia No. 546.2012.4 supporting leading Russian scientific schools.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Laurienzo, P. Marine polysaccharides in pharmaceutical application: An overview. Mar. Drugs 2010, 8, 2435–2465, doi:10.3390/md8092435.
  2. Senni, K.; Pereira, J.; Gueniche, F.; Delbarre-Ladrat, C.; Sinquin, C.; Ratiskol, J.; Godeau, G.; Fischer, A.M.; Helley, D.; Colliec-Jouault, S. Marine polysaccharides: A source of bioactive molecules for cell therapy and tissue engineering. Mar. Drugs 2011, 9, 1664–1681, doi:10.3390/md9091664.
  3. Stonik, V.A.; Fedorov, S.N. Cancer preventive marine natural product. In Cellular and Genetic Practices for Translational Medicine; Kwak, H., Ed.; Research Signpost: Karalla, India, 2011; pp. 1–36.
  4. Beress, A.; Wassermann, O.; Bruhn, T.; Beress, L.; Kraiselburd, E.N.; Gonzalez, L.V.; de Motta, G.E.; Chavez, P.I. A new procedure for the isolation of anti-HIV compounds (polysaccharides and polyphenols) from the marine alga Fucus vesiculosus. J. Nat. Prod. 1993, 56, 478–488, doi:10.1021/np50094a005.
  5. Ponce, N.M.A.; Pujol, C.A.; Damonte, E.B.; Flores, M.L.; Stortz, C.A. Fucoidans from the brown seaweed Adenocystis utricularis: Extraction methods, antiviral activity and structural studies. Carbohydr. Res. 2003, 338, 153–165, doi:10.1016/S0008-6215(02)00403-2.
  6. Ray, B. Polysaccharides from Enteromorpha compressa: Isolation, purification and structural features. Carbohydr. Polym. 2006, 66, 408–416, doi:10.1016/j.carbpol.2006.03.027.
  7. Ye, H.; Wang, K.; Zhou, C.; Liu, J.; Zeng, X. Purification, antitumor and antioxidant activities in vitro of polysaccharides from the brown seaweed Sargassum pallidum. Food Chem. 2008, 111, 428–432, doi:10.1016/j.foodchem.2008.04.012.
  8. Esteves, A.I.S.; Nicolai, M.; Humanes, M.; Gonsalves, J. Sulfated polysaccharides in marine sponges: Extraction methods and anti-HIV activity. Mar. Drugs 2011, 9, 139–153.
  9. Smit, A.J. Medicinal and pharmaceutical uses of seaweed natural products: A review. J. Appl. Phycol. 2004, 16, 245–262, doi:10.1023/B:JAPH.0000047783.36600.ef.
  10. Andrade, L.R.; Leal, R.N.; Noseda, M.; Duarte, M.E.; Pereira, M.S.; Mourao, P.A.; Farina, M.; Amado Filho, G.M. Brown algae overproduce cell wall polysaccharides as a protection mechanism against the heavy metal toxicity. Mar. Pollut. Bull. 2010, 60, 1482–1488.
  11. Berteau, O.; Mulloy, B. Sulfated fucans, fresh perspectives: Structures, functions, and biological properties of sulfated fucans and an overview of enzymes active toward this class of polysaccharide. Glycobiology 2003, 13, 29R–40R, doi:10.1093/glycob/cwg058.
  12. Jiao, G.; Yu, G.; Zhang, J.; Ewart, H.S. Chemical structures and bioactivities of sulfated polysaccharides from marine algae. Mar. Drugs 2011, 9, 196–223, doi:10.3390/md9020196.
  13. Li, B.; Lu, F.; Wei, X.; Zhao, R. Fucoidan: Structure and bioactivity. Molecules 2008, 13, 1671–1695, doi:10.3390/molecules13081671.
  14. Bilan, M.I.; Grachev, A.A.; Ustuzhanina, N.E.; Shashkov, A.S.; Nifantiev, N.E.; Usov, A.I. Structure of a fucoidan from the brown seaweed Fucus evanescens C.Ag. Carbohydr. Res. 2002, 337, 719–730, doi:10.1016/S0008-6215(02)00053-8.
  15. Chizhov, A.O.; Dell, A.; Morris, H.R.; Haslam, S.M.; McDowell, R.A.; Shashkov, A.S.; Nifant’ev, N.E.; Khatuntseva, E.A.; Usov, A.I. A study of fucoidan from the brown seaweed Chorda filum. Carbohydr. Res. 1999, 320, 108–119, doi:10.1016/S0008-6215(99)00148-2.
  16. Li, B.; Wei, X.J.; Sun, J.L.; Xu, S.Y. Structural investigation of a fucoidan containing a fucose-free core from the brown seaweed Hizikia fusiforme. Carbohydr. Res. 2006, 341, 1135–1146, doi:10.1016/j.carres.2006.03.035.
  17. Usov, A.I.; Smirnova, G.P.; Bilan, M.I.; Shashkov, A.S. Polysaccharides of algae. 53. Brown alga Laminaria cicchorioides. Bioorg. Khim. 1998, 24, 382–389.
  18. Shevchenko, N.M.; Anastiuk, S.D.; Gerasimenko, N.I.; Dmitrenok, P.S.; Isakov, V.V.; Zvyagintseva, T.N. Polysaccharide and lipid composition of the brown seaweed Laminaria gurjanovae. Rus. J. Bioorg. Chem. 2007, 33, 88–98, doi:10.1134/S1068162007010116.
  19. Thinh, P.D.; Menshova, R.V.; Ermakova, S.P.; Anastyuk, S.D.; Ly, B.M.; Zvyagintseva, T.N. Structural characteristics and anticancer activity of fucoidan from the brown alga Sargassum mcclurei. Mar. Drugs 2013, 11, 1456–1476, doi:10.3390/md11051456.
  20. Synytsya, A.; Kim, W.J.; Kim, S.M.; Pohl, R.; Synytsya, A.; Kvasnicka, F.; Copikova, J.; Park, Y.I. Structure and antitumour activity of fucoidan isolated from sporophyll of Korean brown seaweed Undaria pinnatifida. Carbohydr. Polym. 2010, 81, 41–48.
  21. Wang, J.; Zhang, Q.; Zhang, Z.; Zhang, H.; Niu, X. Structural studies on a novel fucogalactan sulfate extracted from the brown seaweed Laminaria japonica. Int. J. Biol. Macromol. 2010, 47, 126–131, doi:10.1016/j.ijbiomac.2010.05.010.
  22. Sakai, T.; Kimura, H.; Kojima, K.; Shimanaka, K.; Ikai, K.; Kato, I. Marine bacterial sulfated fucoglucuronomannan (SFGM) lyase digests brown algal SFGM into trisaccharides. Mar. Biotechnol. 2003, 5, 70–78, doi:10.1007/s10126-002-0056-3.
  23. Pomin, V.H. Fucanomics and galactanomics: Marine distribution, medicinal impact, conceptions, and challenges. Mar. Drugs 2012, 10, 793–811, doi:10.3390/md10040793.
  24. Pomin, V.H.; Mourao, P.A. Structure, biology, evolution, and medical importance of sulfated fucans and galactans. Glycobiology 2008, 18, 1016–1027, doi:10.1093/glycob/cwn085.
  25. Chung, H.J.; Jeun, J.; Houng, S.J.; Jun, H.J.; Kweon, D.K.; Lee, S.J. Toxicological evaluation of fucoidan from Undaria pinnatifida in vitro and in vivo. Phytother. Res. 2010, 24, 1078–1083.
  26. Kim, K.J.; Lee, O.H.; Lee, B.Y. Genotoxicity studies on fucoidan from Sporophyll of Undaria pinnatifida. Food Chem. Toxicol. 2010, 48, 1101–1104.
  27. Kim, K.J.; Lee, O.H.; Lee, H.H.; Lee, B.Y. A 4-week repeated oral dose toxicity study of fucoidan from the sporophyll of Undaria pinnatifida in Sprague-Dawley rats. Toxicology 2010, 267, 154–158, doi:10.1016/j.tox.2009.11.007.
  28. Mizuno, T.; Kinoshita, T.; Zhuang, C.; Ito, H.; Mayuzumi, Y. Antitumor-active heteroglycans from niohshimeji mushroom, Tricholoma giganteum. Biosci. Biotechnol. Biochem. 1995, 59, 568–571.
  29. Vishchuk, O.S.; Ermakova, S.P.; Zvyagintseva, T.N. The fucoidans from brown algae of Far-Eastern seas: Anti-tumor activity and structure-function relationship. Food Chem. 2013, 141, 1211–1217.
  30. Wijesekara, I.; Pangestuti, R.; Kim, S. Biological activities and potential health benefits of sulfated polysaccharides derived from marine algae. Carbohydr. Polym. 2011, 84, 14–21, doi:10.1016/j.carbpol.2010.10.062.
  31. Alekseyenko, T.V.; Zhanayeva, S.Y.; Venediktova, S.Y.; Zvyagintseva, T.N.; Kuznetsova, T.A.; Besednova, N.N.; Korolenko, T.A. Antitumor and antimetastatic activity of fucoidan, a sulfated polysaccharide from the Okhotsk sea Fucus evanescens brown alga. Bull. Exp. Biol. Med. 2007, 143, 730–732.
  32. Itoh, H.; Noda, H.; Amano, H.; Zhuaug, C.; Mizuno, T.; Ito, H. Antitumor activity and immunological properties of marine algal polysaccharides, especially fucoidan, prepared from Sargassum thunbergii of Phaeophyceae. Anticancer Res. 1993, 13, 2045–2052.
  33. Kusaykin, M.; Bakunina, I.; Sova, V.; Ermakova, S.; Kuznetsova, T.; Besednova, N.; Zaporozhets, T.; Zvyagintseva, T. Structure, biological activity, and enzymatic transformation of fucoidans from the brown seaweeds. Biotechnol. J. 2008, 3, 904–915, doi:10.1002/biot.200700054.
  34. Shibata, H.; Iimuro, M.; Uchiya, N.; Kawamori, T.; Nagaoka, M.; Ueyama, S.; Hashimoto, S.; Yokokura, T.; Sugimura, T.; Wakabayashi, K. Preventive effects of Cladosiphon fucoidan against Helicobacter pylori infection in Mongolian gerbils. Helicobacter 2003, 8, 59–65, doi:10.1046/j.1523-5378.2003.00124.x.
  35. Park, H.S.; Kim, G.Y.; Nam, T.J.; Deuk Kim, N.; Hyun Choi, Y. Antiproliferative activity of fucoidan was associated with the induction of apoptosis and autophagy in AGS human gastric cancer cells. J. Food Sci. 2011, 76, T77–T83, doi:10.1111/j.1750-3841.2011.02099.x.
  36. Ale, M.T.; Maruyama, H.; Tamauchi, H.; Mikkelsen, J.D.; Meyer, A.S. Fucoidan from Sargassum sp. and Fucus vesiculosus reduces cell viability of lung carcinoma and melanoma cells in vitro and activates natural killer cells in mice in vivo. Int. J. Biol. Macromol. 2011, 49, 331–336, doi:10.1016/j.ijbiomac.2011.05.009.
  37. Foley, S.A.; Szegezdi, E.; Mulloy, B.; Samali, A.; Tuohy, M.G. An unfractionated fucoidan from Ascophyllum nodosum: Extraction, characterization, and apoptotic effects in vitro. J. Nat. Prod. 2011, 74, 1851–1861.
  38. Athukorala, Y.; Ahn, G.N.; Jee, Y.H.; Kim, G.Y.; Kim, S.H.; Ha, J.H.; Kang, J.S.; Lee, K.W.; Jeon, Y.J. Antiproliferative activity of sulfated polysaccharide isolated from an enzymatic digest of Ecklonia cava on the U-937 cell line. J. Appl. Phycol. 2009, 21, 307–314, doi:10.1007/s10811-008-9368-7.
  39. Costa, L.S.; Fidelis, G.P.; Telles, C.B.; Dantas-Santos, N.; Camara, R.B.; Cordeiro, S.L.; Costa, M.S.; Almeida-Lima, J.; Melo-Silveira, R.F.; Oliveira, R.M.; Albuquerque, I.R.L; Andrade, G.P.V.; Rocha, H.A.O. Antioxidant and antiproliferative activities of heterofucans from the seaweed Sargassum filipendula. Mar. Drugs 2011, 9, 952–966, doi:10.3390/md9060952.
  40. Costa, L.S.; Telles, C.B.; Oliveira, R.M.; Nobre, L.T.; Dantas-Santos, N.; Camara, R.B.; Costa, M.S.; Almeida-Lima, J.; Melo-Silveira, R.F.; Albuquerque, I.R.; et al. Heterofucan from Sargassum filipendula induces apoptosis in HeLa cells. Mar. Drugs 2011, 9, 603–614, doi:10.3390/md9040603.
  41. Zhang, Z.; Teruya, K.; Eto, H.; Shirahata, S. Fucoidan extract induces apoptosis in MCF-7 cells via a mechanism involving the ROS-dependent JNK activation and mitochondria-mediated pathways. PLoS One 2011, 6, e27441.
  42. Hyun, J.H.; Kim, S.C.; Kang, J.I.; Kim, M.K.; Boo, H.J.; Kwon, J.M.; Koh, Y.S.; Hyun, J.W.; Park, D.B.; Yoo, E.S.; et al. Apoptosis inducing activity of fucoidan in HCT-15 colon carcinoma cells. Biol. Pharm. Bull. 2009, 32, 1760–1764, doi:10.1248/bpb.32.1760.
  43. Kim, E.J.; Park, S.Y.; Lee, J.Y.; Park, J.H. Fucoidan present in brown algae induces apoptosis of human colon cancer cells. BMC Gastroenterol. 2010, 10, 96, doi:10.1186/1471-230X-10-96.
  44. Yamasaki-Miyamoto, Y.; Yamasaki, M.; Tachibana, H.; Yamada, K. Fucoidan induces apoptosis through activation of caspase-8 on human breast cancer MCF-7 cells. J. Agric. Food Chem. 2009, 57, 8677–8682, doi:10.1021/jf9010406.
  45. Vishchuk, O.S.; Ermakova, S.P.; Zvyagintseva, T.N. Sulfated polysaccharides from brown seaweeds Saccharina japonica and Undaria pinnatifida: isolation, structural characteristics, and antitumor activity. Carbohydr. Res. 2011, 346, 2769–2776, doi:10.1016/j.carres.2011.09.034.
  46. Jin, J.O.; Song, M.G.; Kim, Y.N.; Park, J.I.; Kwak, J.Y. The mechanism of fucoidan-induced apoptosis in leukemic cells: Involvement of ERK1/2, JNK, glutathione, and nitric oxide. Mol. Carcinog. 2010, 49, 771–782.
  47. Aisa, Y.; Miyakawa, Y.; Nakazato, T.; Shibata, H.; Saito, K.; Ikeda, Y.; Kizaki, M. Fucoidan induces apoptosis of human HS-sultan cells accompanied by activation of caspase-3 and down-regulation of ERK pathways. Am. J. Hematol. 2005, 78, 7–14, doi:10.1002/ajh.20182.
  48. Carmeliet, P. Angiogenesis in health and disease. Nat. Med. 2003, 9, 653–660, doi:10.1038/nm0603-653.
  49. Narazaki, M.; Segarra, M.; Tosato, G. Sulfated polysaccharides identified as inducers of neuropilin-1 internalization and functional inhibition of VEGF165 and semaphorin3A. Blood 2008, 111, 4126–4136, doi:10.1182/blood-2007-09-112474.
  50. Cho, M.L.; Lee, B.Y.; You, S.G. Relationship between oversulfation and conformation of low and high molecular weight fucoidans and evaluation of their in vitro anticancer activity. Molecules 2011, 16, 291–297.
  51. Koyanagi, S.; Tanigawa, N.; Nakagawa, H.; Soeda, S.; Shimeno, H. Oversulfation of fucoidan enhances its anti-angiogenic and antitumor activities. Biochem. Pharmacol. 2003, 65, 173–179, doi:10.1016/S0006-2952(02)01478-8.
  52. Teruya, T.; Konishi, T.; Uechi, S.; Tamaki, H.; Tako, M. Anti-proliferative activity of oversulfated fucoidan from commercially cultured Cladosiphon okamuranus TOKIDA in U937 cells. Int. J. Biol. Macromol. 2007, 41, 221–226, doi:10.1016/j.ijbiomac.2007.02.010.
  53. Yang, C.; Chung, D.; Shin, I.S.; Lee, H.; Kim, J.; Lee, Y.; You, S. Effects of molecular weight and hydrolysis conditions on anticancer activity of fucoidans from sporophyll of Undaria pinnatifida. Int. J. Biol. Macromol. 2008, 43, 433–437, doi:10.1016/j.ijbiomac.2008.08.006.
  54. Ye, J.; Li, Y.; Teruya, K.; Katakura, Y.; Ichikawa, A.; Eto, H.; Hosoi, M.; Hosoi, M.; Nishimoto, S.; Shirahata, S. Enzyme-digested fucoidan extracts derived from seaweed Mozuku of Cladosiphon novae-caledoniae kylin inhibit invasion and angiogenesis of tumor cells. Cytotechnology 2005, 47, 117–126, doi:10.1007/s10616-005-3761-8.
  55. Liu, J.M.; Bignon, J.; Haroun-Bouhedja, F.; Bittoun, P.; Vassy, J.; Fermandjian, S.; Wdzieczak-Bakala, J.; Boisson-Vidal, C. Inhibitory effect of fucoidan on the adhesion of adenocarcinoma cells to fibronectin. Anticancer Res. 2005, 25, 2129–2133.
  56. Philchenkov, A.; Zavelevich, M.; Imbs, T.; Zaporozhets, T.; Zvyagintseva, T. Sensitization of human malignant lymphoid cells to etoposide by fucoidan, a brown seaweed polysaccharide. Exp. Oncol. 2007, 29, 181–185.
  57. Jiang, Z.; Okimura, T.; Yokose, T.; Yamasaki, Y.; Yamaguchi, K.; Oda, T. Effects of sulfated fucan, ascophyllan, from the brown alga Ascophyllum nodosum on various cell lines: A comparative study on ascophyllan and fucoidan. J. Biosci. Bioeng. 2010, 110, 113–117, doi:10.1016/j.jbiosc.2010.01.007.
  58. Vishchuk, O.S.; Tarbeeva, D.V.; Ermakova, S.P.; Zvyagintseva, T.N. The structural characteristics and biological activity of fucoidans from the brown algae Alaria sp. and Saccharina japonica of different reproductive status. Chem. Biodivers. 2012, 9, 817–828, doi:10.1002/cbdv.201100266.
  59. Vishchuk, O.S.; Ermakova, S.P.; Zvyagintseva, T.N. The effect of sulfated (1→3)-alpha-l-fucan from the brown alga Saccharina cichorioides Miyabe on resveratrol-induced apoptosis in colon carcinoma cells. Mar. Drugs 2013, 11, 194–212, doi:10.3390/md11010194.
  60. Jeong, B.E.; Ko, E.J.; Joo, H.G. Cytoprotective effects of fucoidan, an algae-derived polysaccharide on 5-fluorouracil-treated dendritic cells. Food Chem. Toxicol. 2012, 50, 1480–1484, doi:10.1016/j.fct.2012.01.034.
  61. Yang, M.; Ma, C.; Sun, J.; Shao, Q.; Gao, W.; Zhang, Y.; Li, Z.; Xie, Q.; Dong, Z.; Qu, X. Fucoidan stimulation induces a functional maturation of human monocyte-derived dendritic cells. Int. Immunopharmacol. 2008, 8, 1754–1760, doi:10.1016/j.intimp.2008.08.007.
  62. Jin, J.O.; Park, H.Y.; Xu, Q.; Park, J.I.; Zvyagintseva, T.; Stonik, V.A.; Kwak, J.Y. Ligand of scavenger receptor class A indirectly induces maturation of human blood dendritic cells via production of tumor necrosis factor-alpha. Blood 2009, 113, 5839–5847, doi:10.1182/blood-2008-10-184796.
  63. Hu, Y.; Cheng, S.C.; Chan, K.T.; Ke, Y.; Xue, B.; Sin, F.W.; Zeng, C.; Xie, Y. Fucoidin enhances dendritic cell-mediated T-cell cytotoxicity against NY-ESO-1 expressing human cancer cells. Biochem. Biophys. Res. Commun. 2010, 392, 329–334, doi:10.1016/j.bbrc.2010.01.018.
  64. Lee, H.; Kim, J.S.; Kim, E. Fucoidan from seaweed Fucus vesiculosus inhibits migration and invasion of human lung cancer cell via PI3K-Akt-mTOR pathways. PLoS One 2012, 7, e50624.
  65. Xue, M.; Ge, Y.; Zhang, J.; Wang, Q.; Hou, L.; Liu, Y.; Sun, L.; Li, Q. Anticancer properties and mechanisms of fucoidan on mouse breast cancer in vitro and in vivo. PLoS One 2012, 7, e43483.
  66. Lee, N.Y.; Ermakova, S.P.; Choi, H.K.; Kusaykin, M.I.; Shevchenko, N.M.; Zvyagintseva, T.N.; Choi, H.S. Fucoidan from Laminaria cichorioides inhibits AP-1 transactivation and cell transformation in the mouse epidermal JB6 cells. Mol. Carcinog. 2008, 47, 629–637, doi:10.1002/mc.20428.
  67. Lee, N.Y.; Ermakova, S.P.; Zvyagintseva, T.N.; Kang, K.W.; Dong, Z.; Choi, H.S. Inhibitory effects of fucoidan on activation of epidermal growth factor receptor and cell transformation in JB6 Cl41 cells. Food Chem. Toxicol. 2008, 46, 1793–1800, doi:10.1016/j.fct.2008.01.025.
  68. Moon, H.J.; Lee, S.H.; Ku, M.J.; Yu, B.C.; Jeon, M.J.; Jeong, S.H.; Stonik, V.A.; Zvyagintseva, T.N.; Ermakova, S.P.; Lee, Y.H. Fucoidan inhibits UVB-induced MMP-1 promoter expression and down regulation of type I procollagen synthesis in human skin fibroblasts. Eur. J. Dermatol. 2009, 19, 129–134.
  69. Moon, H.J.; Lee, S.R.; Shim, S.N.; Jeong, S.H.; Stonik, V.A.; Rasskazov, V.A.; Zvyagintseva, T.; Lee, Y.H. Fucoidan inhibits UVB-induced MMP-1 expression in human skin fibroblasts. Biol. Pharm. Bull. 2008, 31, 284–289, doi:10.1248/bpb.31.284.
  70. Moon, H.J.; Park, K.S.; Ku, M.J.; Lee, M.S.; Jeong, S.H.; Imbs, T.I.; Zvyagintseva, T.N.; Ermakova, S.P.; Lee, Y.H. Effect of Costaria costata fucoidan on expression of matrix metalloproteinase-1 promoter, mRNA, and protein. J. Nat. Prod. 2009, 72, 1731–1734, doi:10.1021/np800797v.
  71. Jintang, S.; Alei, F.; Yun, Z.; Weixu, H.; Meixiang, Y.; Fengcai, W.; Xun, Q. Fucoidan increases TNF-alpha-induced MMP-9 secretion in monocytic cell line U937. Inflamm. Res. 2010, 59, 271–276, doi:10.1007/s00011-009-0095-6.
  72. Cumashi, A.; Ushakova, N.A.; Preobrazhenskaya, M.E.; D’Incecco, A.; Piccoli, A.; Totani, L.; Tinari, N.; Morozevich, G.E.; Berman, A.E.; Bilan, M.I.; et al. A comparative study of the anti-inflammatory, anticoagulant, antiangiogenic, and antiadhesive activities of nine different fucoidans from brown seaweeds. Glycobiology 2007, 17, 541–552.
  73. Hemmingson, J.A.; Falshaw, R.; Furneaux, R.H.; Thompson, K. Structure and antiviral activity of the galactofucans from Undaria pinnatifida. J. Appl. Phycol. 2006, 18, 185–193, doi:10.1007/s10811-006-9096-9.
  74. Makarenkova, I.D.; Deriabin, P.G.; L’vov, D.K.; Zvyagintseva, T.N.; Besednova, N.N. Antiviral activity of sulfated polysaccharide from the brown alga Laminaria japonica against avian influenza A (H5N1) virus infection in the cultured cells. Vopr. Virusol. 2010, 55, 41–45.
  75. Wang, J.; Zhang, Q.; Zhang, Z.; Song, H.; Li, P. Potential antioxidant and anticoagulant capacity of low molecular weight fucoidan fractions extracted from Laminaria japonica. Int. J. Biol. Macromol. 2010, 46, 6–12.
  76. Zhu, W.; Ooi, V.E.; Chan, P.K.; Ang, P.O., Jr. Isolation and characterization of a sulfated polysaccharide from the brown alga Sargassum patens and determination of its anti-herpes activity. Biochem. Cell. Biol. 2003, 81, 25–33.
  77. Teas, J.; Vena, S.; Cone, D.L.; Irhimeh, M. The consumption of seaweed as a protective factor in the etiology of breast cancer: proof of principle. J. Appl. Phycol. 2013, 25, 771–779, doi:10.1007/s10811-012-9931-0.
  78. Ikeguchi, M.; Yamamoto, M.; Arai, Y.; Maeta, Y.; Ashida, K.; Katano, K.; Miki, Y.; Kimura, T. Fucoidan reduces the toxicities of chemotherapy for patients with unresectable advanced or recurrent colorectal cancer. Oncol. Lett. 2011, 2, 319–322.
  79. Ale, M.T.; Mikkelsen, J.D.; Meyer, A.S. Important determinants for fucoidan bioactivity: A critical review of structure-function relations and extraction methods for fucose-containing sulfated polysaccharides from brown seaweeds. Mar. Drugs 2011, 9, 2106–2130, doi:10.3390/md9102106.
  80. Imbs, T.I.; Shevchenko, N.M.; Semenova, T.L.; Sukhoverkhov, S.V.; Zvyagintseva, T.N. Compositional heterogeneity of sulfated polysaccharides synthesized by the brown alga Costaria costata. Chem. Nat. Comp. 2011, 47, 96–97, doi:10.1007/s10600-011-9839-y.
  81. Skriptsova, A.V.; Shevchenko, N.M.; Tarbeeva, D.V.; Zvyagintseva, T.N. Comparative study of polysaccharides from reproductive and sterile tissues of five brown seaweeds. Mar. Biotechnol. 2012, 14, 304–311, doi:10.1007/s10126-011-9413-4.
  82. Anastyuk, S.D.; Shevchenko, N.M.; Nazarenko, E.L.; Dmitrenok, P.S.; Zvyagintseva, T.N. Structural analysis of a fucoidan from the brown alga Fucus evanescens by MALDI-TOF and tandem ESI mass spectrometry. Carbohydr. Res. 2009, 344, 779–787, doi:10.1016/j.carres.2009.01.023.
  83. Bilan, M.I.; Usov, A.I. Structural analysis of fucoidans. Nat. Prod. Commun. 2008, 3, 1639–1648.
  84. Usov, A.I.; Chizhov, A.O. New data on the structure of laminaran from Chorda filum (L.) Lam. and reserve glycans from other brown algae. Russ. Chem. Bull. 1993, 42, 1597–1601, doi:10.1007/BF00699204.
  85. Rioux, L.E.; Turgeon, S.L.; Beaulieu, M. Structural characterization of laminaran and galactofucan extracted from the brown seaweed Saccharina longicruris. Phytochemistry 2010, 71, 1586–1595, doi:10.1016/j.phytochem.2010.05.021.
  86. Menshova, R.V.; Ermakova, S.P.; Anastyuk, S.D.; Isakov, V.V.; Dubrovskaya, Y.V.; Kusaikin, M.I.; Um, B.H.; Zvyagintseva, T.N. Structure, enzymatic transformation and anticancer activity of branched high molecular weight laminaran from brown alga Eisenia bicyclis. Carbohydr. Polym. 2014, 99, 101–109, doi:10.1016/j.carbpol.2013.08.037.
  87. Akramiene, D.; Aleksandraviciene, C.; Grazeliene, G.; Zalinkevicius, R.; Suziedelis, K.; Didziapetriene, J.; Simonsen, U.; Stankevicius, E.; Kevelaitis, E. Potentiating effect of beta-glucans on photodynamic therapy of implanted cancer cells in mice. Tohoku J. Exp. Med. 2010, 220, 299–306, doi:10.1620/tjem.220.299.
  88. Kuda, T.; Yano, T.; Matsuda, N.; Nishizawa, M. Inhibitory effects of laminaran and low molecular alginate against the putrefactive compounds produced by intestinal microflora in vitro and in rats. Food Chem. 2005, 91, 745–749, doi:10.1016/j.foodchem.2004.06.047.
  89. Mantovani, M.S.; Bellini, M.F.; Angeli, J.P.; Oliveira, R.J.; Silva, A.F.; Ribeiro, L.R. beta-Glucans in promoting health: prevention against mutation and cancer. Mutat. Res. 2008, 658, 154–161, doi:10.1016/j.mrrev.2007.07.002.
  90. Miao, H.Q.; Elkin, M.; Aingorn, E.; Ishai-Michaeli, R.; Stein, C.A.; Vlodavsky, I. Inhibition of heparanase activity and tumor metastasis by laminarin sulfate and synthetic phosphorothioate oligodeoxynucleotides. Int. J. Cancer 1999, 83, 424–431, doi:10.1002/(SICI)1097-0215(19991029)83:3<424::AID-IJC20>3.0.CO;2-L.
  91. Liu, Z.; Lv, D.; Liu, S.; Gong, J.; Wang, D.; Xiong, M.; Chen, X.; Xiang, R.; Tan, X. Alginic acid-coated chitosan nanoparticles loaded with legumain DNA vaccine: effect against breast cancer in mice. PLoS One 2013, 8, e60190.
  92. Usov, A.I. Polysaccharides of the red algae. Adv. Carbohydr. Chem. Biochem. 2011, 65, 115–217.
  93. Buck, C.B.; Thompson, C.D.; Roberts, J.N.; Muller, M.; Lowy, D.R.; Schiller, J.T. Carrageenan is a potent inhibitor of papillomavirus infection. PLoS Pathog. 2006, 2, e69, doi:10.1371/journal.ppat.0020069.
  94. Sun, T.; Tao, H.; Xie, J.; Zhang, S.; Xu, X. Degradation and antioxidant activity of κ-Carrageenans. J. Appl. Polym. Sci. 2010, 117, 194–199.
  95. Hu, X.; Jiang, X.; Aubree, E.; Boulenguer, P.; Critchley, A.T. Preparation and in vivo antitumor activity of kappa-carrageenan oligosaccharides. Pharm. Biol. 2006, 44, 646–650, doi:10.1080/13880200601006848.
  96. Zhou, G.; Xin, H.; Sheng, W.; Li, Z.; Xu, Z. In vivo growth-inhibition of S180 tumor by mixture of 5-Fu and low molecular lambda-carrageenan from Chondrus ocellatus. Pharmacol. Res. 2005, 51, 153–157, doi:10.1016/j.phrs.2004.07.003.
  97. Yuan, H.; Song, J.; Li, X.; Li, N.; Dai, J. Immunomodulation and antitumor activity of kappa-carrageenan oligosaccharides. Cancer Lett. 2006, 243, 228–234, doi:10.1016/j.canlet.2005.11.032.
  98. Lins, K.O.; Bezerra, D.P.; Alves, A.P.; Alencar, N.M.; Lima, M.W.; Torres, V.M.; Farias, W.R.; Pessoa, C.; de Moraes, M.O.; Costa-Lotufo, L.V. Antitumor properties of a sulfated polysaccharide from the red seaweed Champia feldmannii (Diaz-Pifferer). J. Appl. Toxicol. 2009, 29, 20–26, doi:10.1002/jat.1374.
  99. Tobacman, J.K. Review of harmful gastrointestinal effects of carrageenan in animal experiments. Environ. Health Perspect. 2001, 109, 983–994, doi:10.1289/ehp.01109983.
  100. Benard, C.; Cultrone, A.; Michel, C.; Rosales, C.; Segain, J.P.; Lahaye, M.; Galmiche, J.P.; Cherbut, C.; Blottiere, H.M. Degraded carrageenan causing colitis in rats induces TNF secretion and ICAM-1 upregulation in monocytes through NF-kappaB activation. PLoS One 2010, 5, e8666.
  101. Cohen, S.M.; Ito, N. A critical review of the toxicological effects of carrageenan and processed eucheuma seaweed on the gastrointestinal tract. Crit. Rev. Toxicol. 2002, 32, 413–444, doi:10.1080/20024091064282.
  102. Weiner, M.L.; Nuber, D.; Blakemore, W.R.; Harriman, J.F.; Cohen, S.M. A 90-day dietary study on kappa carrageenan with emphasis on the gastrointestinal tract. Food Chem. Toxicol. 2007, 45, 98–106, doi:10.1016/j.fct.2006.07.033.
  103. Lahaye, M.; Robic, A. Structure and functional properties of ulvan, a polysaccharide from green seaweeds. Biomacromolecules 2007, 8, 1765–1774, doi:10.1021/bm061185q.
  104. Bilan, M.I.; Vinogradova, E.V.; Shashkov, A.S.; Usov, A.I. Structure of a highly pyruvylated galactan sulfate from the Pacific green alga Codium yezoense (Bryopsidales, Chlorophyta). Carbohydr. Res. 2007, 342, 586–596, doi:10.1016/j.carres.2006.11.008.
  105. Farias, E.H.; Pomin, V.H.; Valente, A.P.; Nader, H.B.; Rocha, H.A.; Mourao, P.A. A preponderantly 4-sulfated, 3-linked galactan from the green alga Codium isthmocladum. Glycobiology 2008, 18, 250–259.
  106. Fernandez, P.V.; Estevez, J.M.; Cerezo, A.S.; Ciancia, M. Sulfated β-d-mannan from green seaweed Codium vermilara. Cabohydr. Polym. 2012, 87, 916–919.
  107. Costa, L.S.; Fidelis, G.P.; Cordeiro, S.L.; Oliveira, R.M.; Sabry, D.A.; Camara, R.B.; Nobre, L.T.; Costa, M.S.; Almeida-Lima, J.; Farias, E.H.; et al. Biological activities of sulfated polysaccharides from tropical seaweeds. Biomed. Pharmacother. 2010, 64, 21–28, doi:10.1016/j.biopha.2009.03.005.
  108. Ji, H.; Shao, H.; Zhang, C.; Hong, P.; Xiong, H. Separation of the polysaccharides in Caulerpa racemosa and their chemical composition and antitumor activity. J. Appl. Polym. Sci. 2008, 110, 1435–1440, doi:10.1002/app.28676.
  109. Kim, J.K.; Cho, M.L.; Karnjanapratum, S.; Shin, I.S.; You, S.G. In vitro and in vivo immunomodulatory activity of sulfated polysaccharides from Enteromorpha prolifera. Int. J. Biol. Macromol. 2011, 49, 1051–1058, doi:10.1016/j.ijbiomac.2011.08.032.
  110. Leiro, J.M.; Castro, R.; Arranz, J.A.; Lamas, J. Immunomodulating activities of acidic sulphated polysaccharides obtained from the seaweed Ulva rigida C. Agardh. Int. Immunopharmacol. 2007, 7, 879–888, doi:10.1016/j.intimp.2007.02.007.
  111. Tabarsa, M.; Han, J.H.; Kim, C.Y.; You, S.G. Molecular characteristics and immunomodulatory activities of water-soluble sulfated polysaccharides from Ulva pertusa. J. Med. Food 2012, 15, 135–144, doi:10.1089/jmf.2011.1716.
  112. Devaki, T.; Sathivel, A.; BalajiRaghavendran, H.R. Stabilization of mitochondrial and microsomal function by polysaccharide of Ulva lactuca on d-galactosamine induced hepatitis in rats. Chem. Biol. Interact. 2009, 177, 83–88, doi:10.1016/j.cbi.2008.09.036.
  113. Sathivel, A.; Raghavendran, H.R.; Srinivasan, P.; Devaki, T. Anti-peroxidative and anti-hyperlipidemic nature of Ulva lactuca crude polysaccharide on d-galactosamine induced hepatitis in rats. Food Chem. Toxicol. 2008, 46, 3262–3267.
  114. Shimura, H.; Itoh, K.; Sugiyama, A.; Ichijo, S.; Ichijo, M.; Furuya, F.; Nakamura, Y.; Kitahara, K.; Kobayashi, K.; Yukawa, Y.; et al. Absorption of radionuclides from the Fukushima nuclear accident by a novel algal strain. PLoS One 2012, 7, e44200.
  115. de Jesus Raposo, M.F.; de Morais, R.M.; de Morais, A.M. Bioactivity and applications of sulphated polysaccharides from marine microalgae. Mar. Drugs 2013, 11, 233–252, doi:10.3390/md11010233.
  116. Talyshinsky, M.M.; Souprun, Y.Y.; Huleihel, M.M. Anti-viral activity of red microalgal polysaccharides against retroviruses. Cancer Cell Int. 2002, 2, 8–14, doi:10.1186/1475-2867-2-8.
  117. Hasui, M.; Matsuda, M.; Okutani, K.; Shigeta, S. In vitro antiviral activities of sulfated polysaccharides from a marine microalga (Cochlodinium polykrikoides) against human immunodeficiency virus and other enveloped viruses. Int. J. Biol. Macromol. 1995, 17, 293–297, doi:10.1016/0141-8130(95)98157-T.
  118. Fabregas, J.; Carcia, D.; Fernandez-Alonso, M.; Rocha, A.I.; Gomez-Puertas, P.; Escribano, J.M.; Otero, A.; Coll, J.M. In vitro inhibition of the replication of haemorrhagic septicaemia virus (VHSV) and African swine fever virus (ASFV) by extracts from marine microalgae. Antiviral Res. 1999, 44, 67–73, doi:10.1016/S0166-3542(99)00049-2.
  119. Huleihel, M.; Ishanu, V.; Tal, J.; Arad, S.M. Antiviral effects of red microalgal polysaccharides on Herpes simplex and Varicella zoster viruses. J. Appl. Phycol. 2001, 13, 127–134, doi:10.1023/A:1011178225912.
  120. Pugh, N.; Ross, S.A.; ElSohly, H.N.; ElSohly, M.A.; Pasco, D.S. Isolation of three high molecular weight polysaccharide preparations with potent immunostimulatory activity from Spirulina platensis, aphanizomenon flos-aquae and Chlorella pyrenoidosa. Planta Med. 2001, 67, 737–742, doi:10.1055/s-2001-18358.
  121. Sun, L.; Wang, C.; Shi, Q.; Ma, C. Preparation of different molecular weight polysaccharides from Porphyridium cruentum and their antioxidant activities. Int. J. Biol. Macromol. 2009, 45, 42–47, doi:10.1016/j.ijbiomac.2009.03.013.
  122. Park, E.J.; Pezzuto, J.M. Antioxidant marine products in cancer chemoprevention. Antioxid. Redox Signal. 2013, 19, 115–138, doi:10.1089/ars.2013.5235.
  123. Gardeva, E.; Toshkova, R.; Minkova, K.; Gigova, L. Cancer protective action of polysaccharide derived from microalga Porphyridium cruentum—biological background. Biotechnol. Biotechnol. Equip. 2009, 23, 783–787.
  124. Choi, W.Y.; Kang, D.H.; Lee, H.Y. Enhancement of immune activation activities of Spirulina maxima grown in deep-sea water. Int. J. Mol. Sci. 2013, 14, 12205–12221, doi:10.3390/ijms140612205.
  125. Ismail, M.F.; Ali, D.A.; Fernando, A.; Abdraboh, M.E.; Gaur, R.L.; Ibrahim, W.M.; Raj, M.H.; Ouhtit, A. Chemoprevention of rat liver toxicity and carcinogenesis by Spirulina. Int. J. Biol. Sci. 2009, 5, 377–387.
  126. Matsuda, M.; Yamori, T.; Naitoh, M.; Okutani, K. Structural revision of sulfated polysaccharide B-1 isolated from a marine Pseudomonas species and its cytotoxic activity against human cancer cell lines. Mar. Biotechnol. 2003, 5, 13–19, doi:10.1007/s10126-002-0046-5.
  127. Sun, C.; Wang, J.W.; Fang, L.; Gao, X.D.; Tan, R.X. Free radical scavenging and antioxidant activities of EPS2, an exopolysaccharide produced by a marine filamentous fungus Keissleriella sp. YS 4108. Life Sci. 2004, 75, 1063–1073, doi:10.1016/j.lfs.2004.02.015.
  128. Heath-Heckman, E.A.C.; McFall-Ngai, M.J. The occurrence of chitin in the hemocytes of invertebrates. Zoology 2011, 114, 191–198, doi:10.1016/j.zool.2011.02.002.
  129. Kozlowski, E.O.; Gomes, A.M.; Silva, C.S.; Pereira, M.S.; de Vilela Silva, A.C.; Pavao, M.S.G. Structure and biological activities of glycosaminoglycan analogs from marine invertebrates: New therapeutic agents? In Glycans in Diseases and Therapeutics; Pavao, M.S.G., Ed.; Springer-Verlag: Heidelberg, Berlin, Germany, 2011; pp. 159–184.
  130. Yin, H.; Du, Y.; Zhang, J. Low molecular weight and oligomeric chitosans and their bioactivities. Curr. Top. Med. Chem. 2009, 9, 1546–1559, doi:10.2174/156802609789909795.
  131. Pomin, V.H.; de Souza Mourao, P.A. Structure versus anticoagulant and antithrombotic actions of marine sulfated polysaccharides. Braz. J. Pharmacogn. 2012, 22, 921–928.
  132. Luo, L.; Wu, M.; Xu, L.; Lian, W.; Xiang, J.; Lu, F.; Gao, N.; Xiao, C.; Wang, S.; Zhao, J. Comparison of physicochemical characteristics and anticoagulant activities of polysaccharides from three sea cucumbers. Mar. Drugs 2013, 11, 399–417, doi:10.3390/md11020399.
  133. Chen, S.; Li, G.; Wu, N.; Guo, X.; Liao, N.; Ye, X.; Liu, D.; Xue, C.; Chai, W. Sulfation pattern of the fucose branch is important for the anticoagulant and antithrombotic activities of fucosylated chondroitin sulfates. Biochim. Biophys. Acta 2013, 1830, 3054–3066, doi:10.1016/j.bbagen.2013.01.001.
  134. Zhang, W.; Wang, J.; Jin, W.; Zhang, Q. The antioxidant activities and neuroprotective effects of polysaccharides from the starfish Asterias rollestoni. Carbohydr. Polym. 2013, 95, 9–15, doi:10.1016/j.carbpol.2013.02.035.
  135. Zhang, Y.; Song, S.; Liang, H.; Wang, Y.; Wang, W.; Ji, A. Enchancing effect of a sea cucumber Stichopus japonicus sulfated polysaccharide on neurosphere formation in vitro. J. Biosci. Bioeng. 2010, 110, 479–486, doi:10.1016/j.jbiosc.2010.05.009.
  136. Sheng, X.; Zhang, N.; Song, S.; Li, M.; Liang, H.; Zhang, Y.; Wang, Y.; Ji, A. Morphological transformation and proliferation of rat astrocytes as induced by sulfated polysaccharides from the sea cucumber Stichopus japonicus. Neurosci. Lett. 2011, 503, 37–42, doi:10.1016/j.neulet.2011.08.003.
  137. Lian, W.; Wu, M.; Huang, N.; Gao, N.; Li, Z.; Zhang, Z.; Zheng, Y.; Peng, W.; Zhao, J. Anti-HIV-1 activity and structure-activity-relationship study of a fucosylated glycosaminoglycan from an echinoderm by targeting the conserved CD4 induced epitope. Biochim. Biophys. Acta 2013, 1830, 4681–4691, doi:10.1016/j.bbagen.2013.06.003.
  138. Liu, C.H.; Lin, Q.X.; Gao, Y.; Ye, L.; Xing, Y.Y.; Xi, T. Characterization and antitumor activity of a polysaccharide from Strongylocentrotus nudus eggs. Carbohydr. Polym. 2007, 67, 313–318, doi:10.1016/j.carbpol.2006.05.024.
  139. Liu, C.; Xi, T.; Lin, Q.; Xing, Y.; Ye, L.; Luo, X.; Wang, F. Immunomodulatory activity of polysaccharides isolated from Strongylocentrotus nudus eggs. Int. Immunopharmacol. 2008, 8, 1835–1841, doi:10.1016/j.intimp.2008.09.005.
  140. Wang, M.; Wang, H.; Tang, Y.; Kang, D.; Gao, Y.; Ke, M.; Dou, J.; Xi, T.; Zhou, C. Effective inhibition of a Strongylocentrotus nudus eggs polysaccharide against hepatocellular carcinoma is mediated via immunoregulation in vivo. Immunol. Lett. 2011, 141, 74–82, doi:10.1016/j.imlet.2011.08.001.
  141. Wang, H.; Wang, M.; Chen, J.; Tang, Y.; Dou, J.; Yu, J.; Xi, T.; Zhou, C. A polysaccharide from Strongylocentrotus nudus eggs protect against myelosuppression and immunosuppression in cyclophosphamide-treated mice. Int. Immunopharmacol. 2011, 11, 1946–1953, doi:10.1016/j.intimp.2011.06.006.
  142. Suna, L.; Zhua, B.; Lia, D.; Wanga, L.; Donga, X.; Muratab, Y.; Xingc, R.; Dongd, Y. Purification and bioactivity of a sulfated polysaccharide conjugate from viscera of abalone Haliotis discus hannai Ino. Food Agric. Immunol. 2010, 21, 15–26.
  143. Azmi, A.S.; Ahmad, A.; Banerjee, S.; Rangnekar, V.M.; Mohammad, R.M.; Sarkar, F.H. Chemoprevention of pancreatic cancer: Characterization of Par-4 and its modulation by 3,3′-diindolylmethane (DIM). Pharm. Res. 2008, 25, 2117–2124, doi:10.1007/s11095-008-9581-8.
  144. Surh, Y.-J. Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic compounds. Mutat. Res. 1999, 428, 305–327, doi:10.1016/S1383-5742(99)00057-5.
  145. Pan, M.-H.; Ho, C.-T. Chemopreventive effects of natural dietary compounds on cancer development. Chem. Soc. Rev. 2008, 37, 2558–2574.
  146. Cerella, C.; Sobolewski, C.; Dicato, M.; Diederich, M. Targeting COX-2 expression by natural compounds: A promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy. Biochem. Pharmacol. 2010, 80, 1801–1815.
  147. Schumacher, M.; Kelkel, M.; Dicato, M.; Diederich, M. Gold from the sea: Marine compounds as inhibitors of the hallmarks of cancer. Biotechnol. Adv. 2011, 29, 531–547, doi:10.1016/j.biotechadv.2011.02.002.
  148. Kiprushina, Yu.O.; Lukyanov, P.A.; Odintsova, N.A. Effect of mytilan on the UV-radiation resistance of marine invertebrate larvae and human lymphocytes. Russ. J. Mar. Biol. 2010, 36, 305–310, doi:10.1134/S1063074010040097.
  149. Kale, V.; Freysdottir, J.; Paulsen, B.S.; Fridjonsson, O.H.; Hreggvidsson, G.O.; Omarsdottir, S. Sulfated polysaccharide from the sea cucumber Cucumaria frondosa affect maturation of human dendritic cells and their activation of allogeneic CD4(+) T cells in vitro. Bioact. Carbohydr. Diet. Fibre 2013, 2, 108–117, doi:10.1016/j.bcdf.2013.09.009.
  150. Borsig, L.; Wang, L.; Cavalcante, M.C.M.; Cardilo-Reis, L.; Ferreira, P.L.; Mourao, P.A.S.; Esko, J.D.; Pavao, M.S.G. Selectin bloking activity of a fucosylated chondroitin sulfate glycosaminoglycan from sea cucumber. Effect on tumor metastasis and neutrophil recruitment. J. Biol. Chem. 2007, 282, 14984–14991, doi:10.1074/jbc.M610560200.
  151. Kawashima, H.; Atarashi, K.; Hirose, M.; Hirose, J.; Yamada, S.; Sugahara, K.; Miyasaka, M. Oversulfated chondroitin/dermatan sulfates containing glcabeta1/iodaalpha1-3galnac(4,6-o-disulfate) interact with L- and P-selectin and chemokines. J. Biol. Chem. 2002, 277, 12921–12930.
  152. Wang, L.; Brown, J.R.; Vaki, A.; Esko, J.D. Heparin’s anti-inflammatory effects require glucosamine 6-o-sulfation and are mediated by blockade of L- and P-selectins. J. Clin. Invest. 2002, 110, 127–136.
  153. Wang, Y.; Su, W.; Zhang, C.; Xue, C.; Chang, Y.; Wu, X.; Tang, Q.; Wang, J. Protective effect of sea cucumber (Acaudina molpadioides) fucoidan against ethanol-induced gastric damage. Food Chem. 2012, 133, 1414–1419, doi:10.1016/j.foodchem.2012.02.028.
  154. Xu, C.X.; Jin, H.; Chung, Y.S.; Shin, J.Y.; Lee, K.H.; Beck, G.R., Jr.; Palmos, G.N.; Choi, B.D.; Cho, M.H. Chondroitin sulfate extracted from ascidian tunic inhibits phorbol ester-induced expression of inflammatory factors VCAM-1 and COX-2 by blocking NF-κB activation in mouse skin. J. Agric. Food Chem. 2008, 56, 9667–9675, doi:10.1021/jf801578x.
  155. Xu, C.X.; Jin, H.; Chung, Y.S.; Shin, J.Y.; Woo, M.A.; Lee, K.H.; Palmos, G.N.; Choi, B.D.; Cho, M.H. Chondroitin sulfate extracted from the Styela clava tunic suppresses TNF-α-induced expression of inflammatory factors, VCAM-1 and iNOS by blocking Akt/NF-κB signal in JB6 cells. Cancer Lett. 2008, 264, 93–100, doi:10.1016/j.canlet.2008.01.022.
  156. Brito, A.S.; Arimateia, D.S.; Souza, L.R.; Lima, M.A.; Santos, V.O.; Medeiros, V.P.; Ferreira, P.A.; Silva, R.A.; Ferreira, C.V.; Justo, G.Z.; et al. Ant-inflammatory properties of a geparin-like glycosaminoglycan with reduced anti-coagulant activity isolated from a marine shrimp. Bioorg. Med. Chem. 2008, 16, 9588–9595, doi:10.1016/j.bmc.2008.09.020.
  157. Belmiro, C.L.; Castelo-Branco, M.T.; Melim, L.M.; Schanaider, A.; Elia, C.; Madi, K.; Pavao, M.S.; de Souza, H.S. Unfractionated heparin and new heparin analogues from ascidians (chordate-tunicate) ameliorate colitis in rats. J. Biol. Chem. 2009, 284, 11267–11278.
  158. Dreyfuss, J.L.; Regatieri, C.V.; Lima, M.A.; Paredes-Gamero, E.J.; Brito, A.S.; Chavante, S.F.; Belfort, R.; Farah, M.E.; Nader, H.B. A heparin mimetic isolated from a marine shrimp suppresses neovascularization. J. Thromb. Haemost. 2010, 8, 1828–1837, doi:10.1111/j.1538-7836.2010.03916.x.
Mar. Drugs EISSN 1660-3397 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert