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Biological responses of algal derived sulfated polysaccharides: an emphasis on cancer prophylaxis.

Introduction

The life on earth is believed to be originated in the aqueous environment of ocean. The versatile biodiversity of marine environment contributes an important role in keeping the balance of both marine and terrestrial ecosystem. Also, it forms an enormous source of both renewable and non-renewable resources which facilitates extensive speciation in all levels of life, from microorganisms to mammals (1). A recent report showed that around half of the global biodiversity has been contributed by the oceans, that is responsible for the production of potent and active biomolecules by marine organisms (2, 3). In short, the ocean forms a major reservoir for diverse bioactive molecules of both biotic and abiotic components (4). More than 13,000 bioactive natural compounds have been characterized from thalassic origin for several applications (5).

The exploitation of natural products in therapeutic arena has opened an increased demand for compounds from marine sources. The bioactive compounds, mainly synthesized as a part of the defense mechanism of marine organisms, involve secondary metabolites such as terpenoids, alkaloids, peptides, steroids, polysaccharides, flavanoids, pigments and so on (6). The pharmacological activities of several of such biomolecules have been unveiled (7). Extensive research is going on in this aspect globally aiming to design novel drugs and treatment modalities for the management of several end stage diseases. Of the compound characterized, only few products are available in the market and several are in pre-clinical stages (8). Apart from medicinal applications they are also been used in cosmetics, nutritional supplements, agrochemicals and molecular probes.

The increased demand of herbal products (due to their lesser side effects and availability) in the pharmaceutical industry has extended the attention of researchers towards thalassic vegetation. A lion's share of this vegetation includes algae family, the primary producers in marine ecosystem, which contribute more than 90% of the marine plants. The algal population is regarded as the ancestors of plant kingdom which has subjected to several modifications during the course of evolution (9).

Various bioactive metabolites from marine algae are widely explored for the development of new drugs (10). The most studied bioactive metabolites of marine algae include brominated phenols, carotenoids, heterocyclics, nitrogen heterocyclics, kainic acids, guanidine derivatives, phenazine derivatives, amino acids and amines, sterols, sulfated polysaccharides and prostaglandins. Marine algae are also rich in dietary fiber, minerals, lipids, proteins, omega-3 fatty acids, essential amino acids and vitamins (11). But not all species of algae have health-promoting and bio active properties, as some are known to produce toxic metabolites that cause neurodegenerative disorders (12).

Seaweed--The 'Marine Foliage'

Marine macroalgae or seaweeds are vegetation seen in the tidal region of the sea. The harsh and dynamic environment of the tidal zone stimulates the production of bioactive compounds for satisfying their structural, functional and defensive needs. Both marine and terrestrial animals feed on algal vegetation and consume these active fractions from seaweeds for meeting their livelihood. A recent report details that, of the 250 macroalgal species that have been commercially utilized worldwide and more than 150 species are edible (13). The report signifies the exploitation of these bioactive components by other trophic levels of the ecosystem. The presence and composition of such bioactive compounds are being employed for the classification of seaweeds. Accordingly, the main criteria for classification include pigmentation, morphology, anatomy, and nutritional, biochemical, physiological composition. Basically the marine macroalgae are classified as three broad groups: i) brown seaweed (Phaeophyceae); ii) red seaweed (Rhodophyceae) and iii) green seaweed (Chlorophyceae) (14). 6000 species are included in red algae, 2000 in brown algae and 1200 in green algae. They are now becoming the economically and ecologically important marine resources. Examples of marine macroalgae from each genus are given in table 1.

Phaeophyta--The Brown Algae

The Phaeophyta, includes more than 2000 species, (15) are entirely marine inhabitants found in rocky shores in cold and temperate water. Their color varies from olive green to dark brown. The coloration is due to the presence of xanthophylls and fucoxanthin that mask other pigments such as chlorophyll and carotinoids (16). All the brown algae are multicellular, neither single celled nor colonized. They are the largest and most complex among seaweeds. The kelps are the largest among them that form prominent underwater forests. In the evolutionary concern brown algae are evolved from unicellular ancestors (17). Because of their soft bodied nature there is a little chance for brown algae to occur as fossils. Some of the reported fossils were declined due to many reasons. But the earliest and most reliable fossils of Pheophyceae come from Miocene diatomite deposits of the Monterey Formation in California (15).

Rhodophyta--The Red Algae

Red algae are the most abundant seaweeds comprising around 6000 species and are usually multicellular commonly attached to rocks or other algae. But there are some unicellular or colonial forms also exist. They have complex structure and life cycle and have phycoerythrin and phycothcyanin as dominant pigments (18). The common characteristics of red algae includes, they are eukaryotes without centrioles and flagella, use floridean polysaccharides as food reserves, have chloroplasts without external endoplasmic reticulum and containing unstacked thylakoids and their accessory pigments are phycobiliproteins (19). There are reports that red algae occur as fossils. A multicellular fossil from arctic Canada, Bangiomorpha pubescens strongly resembles the modern red alga Bangia (20). Some are parasites of other seaweeds. They are rich source of carrageenan and agar and so widely used for industrial applications.

Chlorophyta--The Green Algae

Green algae are found in freshwater, terrestrial and marine habitats and only 10% are marine. They grow on rocks in shallow water and tide pools. Green algae possess photosynthetic pigments such as Chlorophyll a & b with similar content as in higher plants (18). They also contain carotene and the xanthophylls lutein, zeaxanthin and some members posses violaxanthin, neoxanthin and siphonein (15). Chlorophytes evolved more than a billion years ago in the fossil record. Sea lettuce (genus Ulva) species are widespread; from polar to tropical waters.

Chemical Composition of Marine Algae

The presence of high carbohydrate, proteins, essential amino acids, poly unsaturated fatty acids, vitamins and minerals made seaweeds an important component of functional food (21). The structural polysaccharide components of algae such as carrageenan, agar and alginate are being exploited for industrial applications (22). The bioactive compounds and secondary metabolites such as phenolic compounds and organic acids produced by them are important candidates in pharmaceuticals (23). The composition of biomolecules varies with species, maturity, growth environments, geographical locations and harvesting seasons (24).

Seaweeds polysaccharides play structural and storage functions in algae. Seaweed polysaccharides include dietary fibers, sulfated derivatives, hydrocolloids etc. A study of biochemical composition of nine species of marine algae from European temperate Atlantic waters reported that the total polysaccharide content ranges from 4% to 76% of dry weight. The highest amounts were found in Ascophyllum, Porphyra and Palmaria species and were above 70% (25).

Protein content of seaweeds also varies with species. The protein content is high in green and red species (35%-44%) when compared to brown algae. Among browns Undaria species has the maximal content of 24% (25). Red algal varieties and brown algae varieties were reported to contain 26.6 [+ or -] 6.3 g/100 g and 12.9 [+ or -] 6.2 g/100g respectively (26). Also these were detected to have almost all essential amino acids. A comparative study of red, brown and green algal species, showed that soluble proteins ranges from 4.3 [+ or -] 0.4% to 32.4 [+ or -] 2.5% and amino acids from 26.5 [+ or -] 1.9 to 152.3 [+ or -] 4.0 mg/g (22). Algae are potent source of Eicosapentaenoic acid n-3 (27) and n-3 PUFAs also (28). Around 16 different fatty acids were identified in Ulva lactuca, in Sargassum wightii and in Kappaphycus alvarezii (29).

Besides these macromolecules algae also consist of many other molecules including pigments, minerals, vitamins, secondary metabolites such as halogenated and phenolic compounds and some undesirable compounds like heavy metals (25). The list of composition of certain marine macroalgae is given in table 2. Sulfated polysaccharides and their applications are given priority in this article and so the coming session is being dealt with the chemistry of sulfated polysaccharides in marine algae.

Marine algal Sulfated polysaccharides Chemistry and composition

Sulfated polysaccharides are complex group of macromolecules that forms a major part of extracellular matrix in algae (34). The chemical structure of sulfated polysaccharides varies with the species, season and extraction method. So the batch to batch variation in chemical composition and biological activities are common (35). The diverse structure among these saccharides arises due to the difference in monosaccharide composition, varying number of sulfate moieties, and the hydroxyl(s) to which the sulfate group(s) are linked. Amount and molecular weight of sulfated polysaccharides also varies among different species of marine algae. Majorities are existing as fucoidan in brown algae, carrageenan in red and ulvan in green algae (36, 37). Structures of major sulfated polysaccharides in brown, red and green algae are shown in Fig 1-4.

The galactose rich polysaccharides of red algae, also called as galactans, consist of carrageenans and agarans. Carrageenans have D series of a-galactose residues and agarans have L-series (38). Carrageenans have a wide occurrence and are heterogeneous due to their structural variations like difference in sulfation pattern. This difference in number and position of sulfate groups allowed the classification of carrageenans in to 3 main families: kappa (k), iota (i) and lambda (e). Altogether there are about 15 varieties of carrageenans (39). Sulfated polysaccharides found in green algae have diverse structure and chemistry and also they are the most heterogeneous groups of sulfated polysaccharides. This diversity makes it difficult to classify these polysaccharides as in the case of carrageenans (40). One of the most studied green algae for sulfated polysaccharides is Ulva, which contains Ulvan as the major water-soluble polysaccharide. Ulvan composed of sulfate, rhamnose, xylose, iduronic and glucuronic acids as main constituents (41).

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Brown algae derived sulfated polysaccharides are the most studied. Brown algae consist of a group of fucose rich polysaccharides containing sulfate known as fucan, fucosan or sulfated fucan (42). Besides fucose (major component) and sulfate, they also contain other monosaccharides such as mannose, galactose, glucose, xylose and uronic acids. The widely exploited fucan from brown seaweed is fucoidan that found in the cell walls of brown seaweeds. Fucoidan from several species of brown algae have been isolated and that from Fucus vesiculosus has been available commercially for decades. Fucoidan of Fucus vesiculosus contained primarily (1 [right equal to] 2) linked 4-O-sulfated fucopyranose residues where most of the sulfate groups were located at position C-4 of the fucose units (43). Pankter et al revised the structure of fucoidan based on GC/MS data of methylation and suggested that it is composed of a(1 [right equal to] 3) linked fucose with sulfate groups at the C-4 position on some of the fucose residues (44).

Fucans vary in structure even among same algal species due to their high heterogeneity. For example the fucoidan from the brown alga Saccharina cichorioides is 2, 4-disulfated 1, 3-a-L-fucan, while the fucoidan from Fucus evanescens contains blocks of a-1,3-fucooligosaccharides and a-1,4-fucooligosaccharides sulfated at the position 2 in fucose residues (42). In general fucans are classified into two groups; one consists of (1 [right equal to] 3)linked a-L-fucopyranose residues as back bone and another with repeating (1 [right equal to] 3)--and (1 [right equal to] 4)-linked a-L-fucopyranose residues as back bone (45). The fine structure of fucans remains complex and only little structural information is available from NMR due to their structural irregularity, presence of minor compounds such as pentose, hexose and uronic acids and difference in sulfation patterns. Also this heterogeneity in structure contributes to the varied biological activity of this polysaccharide.

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Bioavailability of fucoidan--penetration through gut barriers

The intestinal digestion, absorption and metabolism of fucoidan and other marine polysaccharides are still under debate. Only a few reports are available dealing the bioavailability of fucoidan. Even though the exact mechanism is fully not unveiled yet, there are several hypotheses emerged focusing on the metabolic utilization of such biomolecules. The large molecular weight of fucoidan offers the major issue regarding its absorption and utilization in living systems. The first evidence of the intestinal absorption of orally administrated fucoidan was reported by Irhimeh et al. They detected small amount of orally given fucoidan (from brown algae Undaria pinnatifida) in the plasma samples of human volunteers through quantitative competitive ELISA assay using a novel monoclonal antibody 1B1. They also proposed that the fucoidan as a whole can pass the intestine through endocytosis (46). Tokita, and coworkers measured the amount of fucoidan in serum and urine after oral administration using ELISA assay. They raised a novel monoclonal antibody against the fucoidan isolated from the brown algae Cladosiphano kamuranus for their evaluations (47). In another study, high molecular weight fucoidan was observed in the rat liver after administration through drinking water using immune histochemical staining (48). All these studies have thrown light to the possibilities for the uptake of fucoidan by mammalian system and paved way to the validation of these polysaccharides for cancer management and other therapeutic uses.

Isolation of sulfated polysaccharides from marine algae--current state of art

The extraction techniques used to isolate sulfated polysaccharides have impact on the maintenance of their native structure. For fucoidan, the extraction at room temperature and at 70[degrees]C results in different chemical compositions (49). For sulfated polysaccharides from Sargassum species, the extraction technique optimized is 0.03 M HCl, 90[degrees]C, 4 h (43). Cold acidic extraction is used to extract sulfated polysaccharides from Sargassum plagiophyllum. In this method, after decoloration and defatting the polysaccharides from algal mass is extracted using 0.1M HCl and precipitated using absolute ethanol. Further purification is done by using Q sepharose fast flow column (50). From brown algae U. pinnitafida sulfated polysaccharides are isolated using hot acid extraction method. The dried algal mass is first extracted with 0.4% HCl for 24 hours and then with 0.4% HCl at 60[degrees]C for 6 h. The extracts are combined, concentrated and precipitated using ethanol. Crude polysaccharide is then purified using DEAE-Sephadex A-25 column eluting with a step gradient of 0.1-2M NaCl (51).

For the isolation of sulfated polysaccharides, the algal mass can be subjected to hot water extraction. After removing the fat and pigments through soxhlet extraction, the algal mass is subjected to hot water extraction for 8 h at 75-85[degrees]C. The extracts are concentrated, deproteinated and precipitated with absolute ethanol (52). Crude sulfated polysaccharides from red marine algae Gracilaria ornate was isolated using the protocol described by Amorim et al. Initially the algal powder was subjected to mechanical stirring for 24 h at room temperature, centrifuged, precipitated using absolute ethanol, dialyzed and freeze dried. In the second method, the powder was extracted at 80[degrees]C for 4 h, and then followed the above mentioned steps. Also the powder was extracted at 80[degrees]C for 4 h twice which showed more yield (53).Water-soluble sulfated polysaccharides from red algae Sphaerococcus coronopifolius and Boergeseniella thuyoides also can be isolated using hot water extraction technique (54).

Fucoidan from brown algae are commonly extracted using deionized water, hydrochloric acid (HCl) and calcium chloride (Ca[Cl.sub.2]). Yang et al. extracted fucoidan using deionized water. The method includes depigmentation, defatting and deproteination using 85% ethanol and acetone which was followed by extraction with hot water and finally precipitation with 70% ethanol (55). In acid extraction, HCl is used instead of water after depigmentation, defatting and deproteination (37). In salt extraction, methanol, chloroform and water are used to remove fat, protein and color pigments and then polysaccharides are extracted using Ca[Cl.sub.2] at 85[degrees]C (56). Commonly used methods and protocols for the isolation of sulfated polysaccharide are summarized in Fig 5.

Seaweed polysaccharides for biomedical applications

The diversity in marine biomolecules has also been explored for several novel biological applications like tissue engineering and therapeutic drug delivery. The recent and advanced developments in the field of biomaterials have thrown light to utilize marine ecosystem for the welfare of mankind. Even though marine biomaterials are derived from different organisms, those obtain from the algal sources bear largest marine biomass and are biologically, economically and nutritionally promising (57). Marine derived biomolecules like carbohydrates, proteins and lipids has been investigated for several biomedical applications. The polysaccharides such as alginate, chitin, chitosan, carrageenans, fucoidan, agar etc. which form structural components of their cell wall (58). were exploited for several biomedical applications. Due to their negative charge the sulfated polysaccharides are ideal for blood contacting materials and cell growth (59, 60).

The increased scarcity of donor for organ transplantation and immune rejection and associated complications has led the evolution of a new approach of tissue engineering (61, 62). Tissue engineering aims at the in vitro assembly of an organ as a whole or a part of the same by combining biomaterial scaffolds and cells from the tissues of interest (63). A classical definition for tissue engineering was given by Langer and Vacanti, as an interdisciplinary field of engineering and life science for the development of biological substitutes that can restore, maintain or improve tissue or organ function (64). The porous structured scaffolds will provide sufficient room for eliciting the biological response of the seeded cells (65). At the target site the scaffolds will get degraded, leaving behind a functional tissue which will ultimately get integrated with the host and become functional (58).

Polymers from natural and synthetic origin or a combination of both has been employed as scaffolds for various tissue engineering applications (66). For example, Hyaluronic Acid (HA) from various natural source is widely used for tissue engineering scaffolds due to its supportive role in cell proliferation and differentiation (67). It was reported that synthetic polymers such as poly-orthoesters, polycarbonates, poly-anhydrides and poly-phosphazenes have wild applications in tissue engineering (68). Glycosaminoglycans, due to their low immunogenicity and ability to interact with growth factors through their sulfate groups, earned more attention as potential scaffolds for various tissue engineering applications (69). The effect of sulfate groups in cellular proliferation (69), differentiation (70) and signaling (71) has given priorities to marine sulfated polysaccharides. Brown seaweeds are rich source of polysaccharides such as alginate, laminarins and sulfated fucans (40, 72).

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Biomedical composite scaffolds consisting of poly (acaprolactone) (PCL) and fucoidan (Fu) is reported as a potential scaffold for bone tissue regeneration. The fucoidan content increased hydrophilicity and mechanical properties (73). Fucoidan was also found to stimulate production of hepatocyte growth factor (HGF) which has key roles in tissue regeneration (74). Another study showed the application of fucoidan for bone regeneration and designing of bone substitutes. Fucoidan mediated osteoblast proliferation, collagen type I expression, mineral deposition and alkaline phosphatase activity has added extra benefits to these polysaccharides (75). A macro porous fucoidan based scaffold was also proven to be an ideal biomaterial for cardiac differentiation from human Embryonic Stem Cells (hESCs) (76).

Ulvan, sulfate containing polysaccharide from green algae also has wide application in tissue engineering. Combination of ulvan with poly-D, L-lactic acid (PDLLA) has improved the biological responses for bone regeneration (77, 52). Alginate is one of the best known material for tissue engineering due to their physiochemical properties and tunable release profile (65, 78). Alginate based scaffolds have been hailed for their biocompatibility and is being used for the engineering of tissues like heart (59), bone (79), cartilage (80), neurons (81), liver (82), pancreas (83) and so on.

Wound dressings using biomaterials are now widely used as they can involve in normal wound healing and new tissue formation. Natural polymers such as collagen, hyaluronic acid, chitosan, alginates and elastin are commonly used for manufacturing wound dressings (84). Polysaccharides from marine algae such as fucoidan and alginate were reported to possess wound healing property. Alginate dressings using calcium alginate from brown algae is the most studied component for wound healing and are biodegradable that can be easily removed without disturbing the healing granulation tissue (85). On contact with the wound, dressing material turns into gel that maintains a physiologically moist environment necessary for wound healing (86). Alginate is an effective haemostat which is well tolerated by body tissues. Alginate based wound dressings displayed better epidermal healing on a series of wounds tested. The effect of calcium alginate dressing in wound healing studied in vitro by Doyle et al showed that an increased proliferation of fibroblasts. The release of calcium ions can also promote various aspect of wound healing (87). Moreover alginate containing dressings have the capacity to activate macrophages to produce tumor necrosis factor-a (TNF a), 86. and also can be effectively used as a haemostatic agent for cavity wounds (88). Fucoidans have been shown to enhance wound healing by modulating the effects of a variety of growth factors similar to the action of heparin. Fucoidan modulates the effect of Transforming Growth Factor (TGF)-a and increase the rate of fibroblast repopulation of the wound (89). Fucoidan prevents inflammation by inhibiting gelatinase A secretion and stimulating stromelysin-1 induction (90). The sulfated polysaccharide isolated from two algae species P tetrastromatica and P. boergesenii enhanced collagen formation and deposition and epidermal regeneration in vivo rat models (91). These healing properties of fucoidans can be exploited for the management of wounds especially during implantation by incorporating it in the scaffold backbone.

Polysaccharides such as fucoidan and alginate from marine algae have been used in drug delivery applications also. These biopolymers are superior in protecting the drug molecules from enzymatic degradation and enable self-administration (92). Microencapsulation of susceptible drugs with biopolymers is widely used for their oral delivery ensuring the sustained release of drug at the target site (93). A sulfated fucan--Xylofucoglucuronan --from Spatoglossum schroederi algae is effective for the immobilization and controlled release of antibiotics gentamicin and amikacin (94). Curcumin loaded pH responsive chitosan-fucoidan nanoparticle was proven to be a potential oral delivery system (95). Alginate based microsphere loaded with fluorescently labeled immunoglobulin G (IgG) retained the bioactivity prior and post release (96).

Iron oxide nanoparticles ([Fe.sub.3][O.sub.4]-NPs) were synthesized by reduction of ferric chloride solution with brown seaweed, Sargassum muticum water extract. The sulfated polysaccharide present in the extract acts as reducing agent and efficient stabilizer in the green biosynthesis of this nanoparticle (97). Biologically synthesized gold nano particles (AuNPs) from marine macroalgae, Padina gymnospora also showed potential antitumor activity in a lung and liver tumor system in vitro (98). A nanocoating containing the layer by layer assembly of Chitosan with sulfated polysaccharide, [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] was found to improve cell proliferation, ALP activity and bio-mineralization (99).

Thus, other than the therapeutic applications, seaweeds also contribute to humans as biomaterials. There is an increased demand for these types of innovation especially in the field of regenerative medicine. But technological challenges mainly in the case of extraction and purification of active compounds make these as tedious tasks.

Seaweeds as Phytomedicine Reservoir

Seaweeds are widely used for edible, medicinal and industrial purposes due to their physiochemical, biological and mechanical properties (100). There was a great explosion in the exploration of marine environment during early 1970s (101). Last 40 years witnessed an immense development in the marine research especially in the area of marine pharmaceuticals. Recent increase in the demand for marine pharmaceutical products in the global market forms substantial evidence. Several marine based drugs got Food and Drug Administration (FDA) approval recently and hundreds of natural products are under clinical trials (102). The increasing demand for herbal medicines opened new opportunities for seaweed based pharmaceutics. The board spectrum of biological activities exhibited by seaweeds can be attributed to the different bioactive molecules synthesized by them (5).

The initial research was mainly focused on marine algal terpenoids. The chemical investigation of terpenoid like compounds have led to the isolation of many other bioactive merabolites including brominated, nitrogenated and oxygenated heterocycles, phenazine derivatives, sterols, amino acids, amines, flavonoids, guanidine derivatives and so on (103). As these compounds conferred several biological activities secondary metabolites form the basis of many recent drugs. Some of these properties are described in the following sections.

Antioxidant activity

Free radicals, Reactive oxygen species (ROS) and Reactive Nitrogen Species (RNS), are highly unstable molecules having unpaired electrons in their outer most shell (104, 105, 72). Due to the utilization of molecular oxygen in all aerobic cells undergoing oxidative phosphorylation, ROS are produced by elements of TCA cycle, protein components of ETC, and some enzymes such as monoamine oxidase in mitochondria. Also they are produced by microsomes, peroxisomes, and some cytosolic enzymes such as xanthin oxidase, cytochrome P450 reductase and NADPH oxidases (106). Reactive nitrogen species (RNS) include NO radical and their related species such as peroxynitrite anion (ONOO-). NO radical is generated from guanido nitrogen of L-arginine by nitric oxide synthase in the cell (107). These reactive species produced at a basal level by biological reactions can be effectively managed by cellular antioxidant defense system. At an increased concentration, these are highly toxic to biological system and cause oxidative damage to DNA, lipids, proteins and carbohydrates. The diseases like cancer, heart diseases, diabetes etc. were reported to be mediated through ROS (108).

Antioxidants protect from oxidative damage. Human body has a well organized system of antioxidants involving both from endogenous and exogenous origin (109). Endogenous antioxidants mainly involve antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and glutathione reductase (GR) that catalyze free radical scavenging reactions. Exogenous molecules like ascorbic acid (vitamin C), tocopherols, tocotrienols, carotenoids, polyphenols, flavanoids, alkaloids and curcuminoids are mainly supplemented through diet. All these mechanisms help the body to neutralize free radicals and to protect from oxidative stress either directly or by activating the endogenous antioxidants (105). Apart from this, several synthetic antioxidants such as butylated hydroxyl anisole (BHA), butylated hydroxyl toluene (BHT), Propylgallate (PG) and tertiary butyl hydroquinone (TBHQ) are commercially available. But toxicity studies warned that the use of these synthetic compounds in food results in carcinogenesis and liver damage (110). So the antioxidants from natural sources are ideal choice. Similar to terrestrial sources, the thalassic resources especially marine algae were also found to be rich source of antioxidants (111, 112).

Like all other photosynthetic plants, the marine algae are also under high oxygen concentration which induces the generation of oxidants that damage the photosynthetic apparatus made of poly unsaturated fatty acids (PUFA) (113). As a protective measure, the algae synthesis potential antioxidant compounds (112). Terpenoids, phlorotannins, polyphenols, phenolic acids, anthocyanins, hydroxycinnamic acid derivatives, sulfated polysaccharides and flavonoids are the important antioxidant compounds in macroalgae (114). Major antioxidant compounds isolated from algal sources are presented in table. 3. The search for newer antioxidants and the active fractions and derivatives of the existing ones still continues to explore the active antioxidant repository in marine algae.

Sulfated polysaccharides from marine algae have been widely studied for their antioxidant ability. Recent studies have thrown light to the potent antioxidant activities of sulfated polysaccharide from seaweeds. For instance the sulfated polysaccharide from brown sea algae Sargassum horneri exhibited excellent superoxide and hydroxyl radical scavenging properties and substantial reducing power (116). De Souza et al compared in vitro antioxidant activities of iota, kappa and lambda carrageenans from red algae with fucoidan from brown seaweed Fucus vesiculosus. With respect to the inhibition of superoxide radical formation, fucoidan had a superior effect than others (117). Red seaweed Gracilaria birdiae also exhibited considerable free radical scavenging activity (118).

The antioxidant activity was reported to be influenced by sulfate content. The polysaccharides with intermediate molecular weight were reported to be superior antioxidants when comparing with low and high molecular weight ones (116). Highly sulfated ulvans possess effective scavenging activity on hydroxyl radical, stronger reducing power and better iron chelating potential than natural ulvans (119). Ulvan from U. pertusa and their acetylated and benzoylated derivatives were also found to be efficient in scavenging ROS (119). Similar responses were exhibited by sulfated polysaccharide from the brown seaweed Dictyopteris delicatula. The ferric chelating activity and reducing power were comparable to that of vitamin C. Moreover it was proposed that several sulfated polysaccharides of D. delicatula may act synergistically to promote more efficient superoxide radical scavenging effects (94). Chattopadhyay et al reported that fucoidan showed the highest antioxidant activity followed by alginate and laminarans from brown alga Turbinaria conoides (120). The molecular and chemical mechanisms behind the anti-oxidant effects of sulfated polysaccharides are unknown yet. The involvement and effect of sulfated groups in scavenging ROS is also needs to be studied in detail.

Antimicribial activity

Algae are also capable of producing anti-microbial compounds that resist infectious microbes. Brominated phenols, terpenoids, sterols, polysaccharides, peptides and proteins form a lion's share of anti-microbial compounds of marine algal origin (121). Haloforms, halogenated alkanes and alkenes, alcohols, aldehydes, hydroquinones and ketones are also proven antimicrobial agents (122). Some of the major antimicribial compounds of marine algal origin are given in table. 4.

There are reports projecting that extracts from brown algae show more antibacterial activity than red and green algae (134, 135). Depsipeptides kahalalide A and F from Bryopsis species were proven to arrest the proliferation of Mycobacterium tuberculosis (136). Chronic Pseudomonas aeruginosa infections were cured by halogenated furanone or fimbrolide, a class of lactones, from Delisea pulchra (137). The bactericidal effects of yengaroside-A, a steroidal glycoside isolated from the green algae Codium iyengarii, was confirmed to be active against a broad range of bacteria (138). Sulfated polysaccharides from red algae Kappaphycus alvarezii and Gracilaria ornate and from the brown algae Sargassum swartzii exhibited antibacterial activity against E. coli strains which are resistant to ampicillin (139, 140, 53).

Marine algae are also beneficial for fungicidal properties. The presence of halogen functional groups makes them a superior antifungal agent. The red algae predominate in this aspect than other two classes. Pholorotannins, phenolic compounds and cliterpenediol (crinitol) produced by brown algal species like Sargassum critaefolium, S. tortile, Ecklonia kurome, E. bicyclis and Cystoseira crinite are efficient antifungal agents (141). The marine algae Stocheospermum marginatum exhibited fungicidal effects against Aspergillus niger (121).

Certain seaweeds are found to be effective against C. lagenarium, a fungus that cause a post-harvest infection Anthracnosein in agricultural plants. In a study regarding the evaluation of antifungal effect of certain seaweeds it was found that P. canaliculata, S. muticum, S. zonale, A. nodosum, F. spiralis and L. dendroidea extracts contained substances that inhibited the growth of C. lagenarium (142). The addition of powder of brown algae: Stokeyia indica, Padina pavonia and red algae: Solieria robusta to the soil improved the soil quality. The treatment with algal powder protected the plant Abelmoschus esculentus (okra) from root infections by the fugal strains Macrophomina phaseolina, Rhizoctonia solani and Fusarium solani (143). Also the brown algae, Stoechospermum marginatum and Sargassum tenerrimum arrested the growth of fungus Meloidogyne javanica that causes root infections (144).

Natural products from marine algae are also found to be effective against many human viral infections without inducing many side effects. A novel sphingosine derivative from green algae Ulva fasciata has been hailed for its in vivo antiviral activity (145). Galactan sulphate from Aghardhiella tenera (146) and xylomannan sulphate from Nothogenia fastigiata (147, 148) were found to be effective against human immunodeficiency virus (HIV), Herpes simplex virus (HSV) types I and II, respiratory syncytial virus (RSV) and so on. Mazumdera et al. proved similar mechanism of action for high molecular weight galactan sulphate from Gracilaria acorticata (149). Anti-herpetic activities of Carrageenans from cystocarpic and tetrasporophytic stages of Stenogramme interrupta were also reported to be significant (150).

Polyanionic saccharides such as heparin inhibit the viral attachment to the host cell surface by making a negatively charged complex with the viral particle (151). This paved way for the exploration of polyanionic sulfated polysaccharides for their antiviral activity. Carrageenans and galactans are the important sulfated polysaccharides in red algae. A carrageenan from Gymnogongrus griffithsiae and a galactan from Cryptonemia crenulata were also reported to inhibit multiplication of DENV2 in Vero cells (152). Sulfated xylomannans from the red seaweed Sebdenia polydactyla inhibits the propagation of HSV-1. These evaluations confirmed the significance of sulfation in antiviral potential (153). Sphingosine derivative from the green alga Ulva fasciata showed both in vitro and in vivo virucidal activity (145). The branched sulfated hetero- rhamnan from the green seaweed Gayralia oxysperma has specificity against herpes simplex virus (154).

Fucans, sulfated polysaccharide from brown algae, were also found to possess antiviral activity against different types of human viruses. The reverse transcriptase activity of HIV was found to be inhibited by the sulfated fucans from the seaweed species Dictyota mertensii, Lobophora variegata, Spatoglossum schroederi and Fucus vesiculosus (155). The galactofucans isolated from the brown seaweedAdenocystis utricularis showed a potent inhibitory activity against herpes simplex virus 1 and 2, with no cytotoxicity (49).

Fucoidan, a fucose containing sulphated polysaccharide from brown algae, exhibits antiviral property by inhibiting the attachment of virus to the host cell (156). The mechanism of fucoidan action is similar to that of heparin. The in vitro study of antiviral effect of fucoidan showed its effectiveness against poliovirus II, adenovirus III, ECHO 6 virus, Coxsackie B 4 virus and Coxsackie A 16 virus by inhibiting the cytopathic effect (157). Fucoidan, from Cladosiphon okamuranus arrest dengue virus type 2 (DEN2) infections. Removal of sulfate group and conversion of glucoronic acid to glucose significantly attenuated their inhibitory activity on DEN2 infection. That is both the sulfate group and glucuronic acid of fucoidan account for the inhibition of DEN2 infection (158). In another study fucoidan, isolated from an edible brown alga Undaria pinnatifida, was shown to be a potent inhibitor of in vitro and in vivo replication of herpes simplex virus type 1 (HSV-1). In in vitro studies phagocytic activity of macrophages and B cell blastogenesis were found to be stimulated by fucoidan. Oral administration of the fucoidan protected mice from infection with HSV-1 by the augmentation of NK activity (159).

Antiinflammatory activity

Inflammation is a localized protective reaction of the body evolved in higher organisms in response to allergic or chemical irritation, injury and/or infections, immune reactions, and other noxious conditions. The inflammatory response is associated with symptoms such as pain, heat, redness, swelling and loss of function of affected area. The chemical mediators released during the inflammatory process play important role to recruit and activate other cells to the site of inflammation (160). Inflammation can be acute or chronic. The acute inflammation is of short duration while that of chronic is prolonged. The chronic inflammation is associated with pathogenesis and progression of all inflammatory diseases including cancer, cardiovascular disease (CVD), stroke, renal failure, neurological disorders, and chronic obstructive pulmonary disease (COPD) (161). The treatment with brown algae Sargassum micracanthum extracts suppressed the pro-inflammatory cytokines, (inducible nitric oxide synthase) iNOS, and cyclooxygenase (COX-2) expression in RAW 264.7 macrophages. The hexane and chloroform fractions of S. micracanthum showed dose dependent decreases in the production of iNOS and COX-2 proteins and iNOS and COX2 mRNA expression. ELISA and RT-PCR assays for TNF-a, IL-1[beta], and IL-6 in LPS stimulated RAW 264.7 cells also displayed similar results. Phlorofucofuroeckol A, a phlorotannin, from Ecklonia stolonifera significantly inhibited the LPS-induced production of NO and PGE2 through the down-regulation of inducible nitric oxide synthase and cyclooxygenase 2 protein expressions (162). The chloroform fraction of D. dichotoma extract was also effective in inhibiting LPS-induced NO and PGE2 production in RAW 264.7 cells. The cells showed a decrease in the expression of iNOS and COX-2 proteins and iNOS and COX-2 mRNA in dose-dependent pattern (163). Similar activity was exhibited by the brown algae Petalonia binghamiae (Miyeoksoi) (164).

Marine red algae especially Gracilaria species were widely exploited for their anti- inflammatory activity (165). Aqueous extract of G. tenuistipitata was reported to suppress viral induced inflammatory response (166). The methanolic extract of Neorhodomela aculeate enhanced the inhibition of cellular reactive oxygen species (ROS) generation, [H.sub.2][O.sub.2]-induced lipid peroxidation and inducible nitric oxide synthase. This showed their antiinflammatory effects at the cellular level (167). Methanolic extracts of Ulva conglobata and U. lactuca were also proven to resist the inflammatory responses (168, 169). The treatment with beta-carotene isolated from green algae Dunaliella bardawil resisted the acetic acid-induced small bowel inflammation in rats (170). Alginic acid from Sargassum wightii also exhibited in vivo antiinflammatory effect in rats (171, 59). Studies by Kim et al revealed the antiinflammatory activities of ethanolic extract of Ishige okamurae was mediated through the inhibition of NF-kappa B (172). Phloroglucinol from brown algae was reported to have antiinflammatory effect on LPS stimulated cells (173).

The sulfated polysaccharides from marine algal sources were also found to possess anti-inflammatory activity. The oral administration of sulphated polysaccharides from brown alga Turbinaria ornate showed antiinflammatory effect against carrageenan-induced paw edema in rats in a dose -dependent manner (174). A water soluble acidic polysaccharide obtained from Ulva rigida modulated the secretion of pro inflammation mediators, cytokines and receptors in RAW 264.7 macrophage. Also there was an increase in secretion of NO and PGE-2 and increase in expression of iNOS, COX-2, IL-12 and TNF-a by macrophage cell lines upon treatment with this polysaccharides (175).

Fucoidan from brown algae inhibited the release of nitric oxide (NO) in LPS activated RAW264.7 cells by down regulating iNOS gene. Fucoidan selectively suppress AP-1 activation which is essential for the induction of iNOS in activated macrophages 176.. Moreover the fucoidan treatment significantly inhibits excessive production of nitric oxide (NO) and prostaglandin E2 (PGE2) in EPS-stimulated BV2 microglia cells also. Attenuation of iNOS, COX-2, MCP-1, and pro-inflammatory cytokines, including interleukin-1b and tumor necrosis factor-alpha (TNF-a) expression signifies the immunomodulatory effects of fucoidan. The suppression of nuclear factor-kappa B(NF-eB) and down-regulation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and AKT pathways by fucoidan also implies the antiinflammatory effects (177).

Anticoagulant activity

Blood coagulation is a complex process that involves a cascade of reactions and a number of coagulation factors. Anticoagulants prevent undesired blood clotting by interacting with these factors. Heparin (a glycosaminoglycan extracted from porcine tissues) is the widely used antithrombotic/anticoagulant drug. But the use of heparin is also have some adverse side effect such as thrombocytopenia, hemorrhagic effect and not effective for acquired anti-thrombin deficiencies (35). Researchers are now focusing on other natural anionic anticoagulants. Many of the negatively charged molecules from marine algae possess anticoagulant activity as they act like heparinoid like compounds. Sulfated polysaccharides from marine brown algae are widely focused (178).

Chemically degraded fucoidan from Pelvetia canaliculata, was reported to have anticoagulant property by inhibition of Factor Ila and Factor Xa in the presence of antithrombin III or heparin cofactor II (179). From the brown seaweed Ecklonia kuromean alpha-L-fucose-rich, sulphated polysaccharide was isolated and reported to have potent anticoagulant activity (180). Fucoidan extracted and purified from the sporophyll of Korean Undaria pinnatifida showed anticoagulant activity in a dose-dependent manner (181). Sulphated fucans isolated from Fucus vesiculosus and Ascophyllum nodosum has many advantages over conventionally used anticoagulants like heparin, as they overcome the antigenic effects. The isolated sulfated fucans exhibited concentration dependent inhibition of thrombin induced platelet aggregation (182). In another study, the marine brown algae Sargassum tenerrimum, Sargassum wightii, Turbinaria conoides, Turbinaria ornate and Padina tetrastromatica collected from Mandapam Island, India showed considerable anticoagulant activity (179).The sulphated polysaccharides extracted from Turbinaria ornate are also potent anticoagulants. The maximum Activated Partial Thromboplastin Time activity recorded at 1125 sec from 1000ig/ml. In the Prothrombin Time activity, the maximum of 81 sec recoded at 1000i g/ml 183..

Ulvan, a sulphated polysaccharide from green algae Ulva species with a heparinoid like structure act by inhibiting intrinsic coagulation pathway and the conversion of fibrinogen into fibrin (184). The sulfated polysaccharide isolated from the marine green algae Monostroma latissimum exhibited high anticoagulant activities as determined by activated partial thromboplastin time (APTT) and thrombin time (TT) (185). An anticoagulant composing galactose with a small amount of glucose, from marine green algae Codium cylindricum, showed similar activities like that of heparin (186). Sulfated polysaccharides from the green algae Ulva conglobata can directly inhibit thrombin and the potentiated heparin cofactor II (187).

Carrageenans from marine red algae also possess high anticoagulant activity (188). Crude sulfated polysaccharide fractions from the red marine alga Halymenia floresia activated partial thromboplastin time (APTT) and thrombin time (TT) using normal human plasma. The mechanism suggested that the activity is through inactivation of thrombin (189). The sulfated polysaccharide from the red-marine-algae Champia feldmannii exhibited anticoagulant activity by extending human plasma coagulation time by 3 times (190).

Immunomodulatory activity

Immune system is a complex and sophisticated defense machinery of the body to fight against foreign invaders. It consists of a set of organs, cells and other molecules. Immunomodulation refers to the induction, expression, amplification or inhibition of any part or phase of the immune response that can affect immune function. Immunomodulators are the substances that modulate and potentiate immune system to fight against adverse conditions such as pathogens or tumors (191). The development of tumor may not be directly related to host immune system, but it has a role in the recovery of the tumor patient. The prevention and cure of neoplastic diseases depends on immunomodulation through natural or synthetic substances as an alternative (192). Owing to the risk of side effects, the conventional drugs are being replaced by natural products. The immunopharmacology and oncology fields are now searching for new bioactive compounds that can stimulate immune system. Marine algae, the rich source of sulfated polysaccharides have proven to possess immunomodulatory effects. But only a few reports have come out regarding their role in immunomodulation. They mainly act by modulating macrophages and also by the production of cytokines.

Sulfated polysaccharides of green algae Capsosiphon fulvescens strongly stimulated macrophage cell line RAW264.7 by producing considerable amounts of NO, PGE2 and cytokines (193). In vitro and in vivo immunomodulatory activities of water-soluble sulfated polysaccharides extracted from Enteromorpha prolifera were determined and reported to have potent activity. These polysaccharides evoked stimulation of immune responses like macrophage and T cell activation by up regulating Th-1 response and increase in IFN- a and IL-2 secretion levels (194). An acidic water soluble polysaccharide obtained from the cell walls of green algae Ulva rigida induced more than two fold increase in the expression of IL6 signal transducer and IL12 receptor beta-1. It also stimulated RAW264.7 murine macrophage and increased their secretion of nitrite, PGE2 and induced an increase in COX-2 and NOS-2 expression (175).

Water and acid soluble polysaccharides were isolated from the red algae Porphyra yezoensis, which also exhibited similar responses in vitro and in vivo. The acid fraction increased the carbon clearance activity of phagocytes both in vitro and in vivo (195). Another study on the structure-function relationship of acidic polysaccharide from the same algae revealed that the sulfate groups contributed to the macrophage stimulating activity (196). The water soluble polysaccharide isolated from red algae, Gracilaria verrucos showed in vivo macrophage stimulating activity on both oral and intraperitonial administration to rats. The IP administration increased the number of peritoneal exudate cells (PEC), the phagocytic activity and ROS scavenging activity of the PEC and stimulates splenic macrophages (197). Sulfated polysaccharide from the red algae Champia feldmannii act as an immunomodulatory agent by increasing the production of specific antibodies (198).

Fucoidan upregulated interferon (IFN)-a and IL- 12 expression in response to a strain of lactic acid bacteria, Tetragenococcus halophilus KK221 in Peyer's patch cells and spleen cells in vitro. The oral administration regulated T Helper cells1/2 Th1/ Th2 balance (199). Fucoidan proved its role in immune stimulation and maturation of dendritic cells (DCs). Fucoidan stimulated the production of interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-a) and major histocompatibility complex (MHC) class I, class II, CD54, and CD86 molecule 200.. The hot water extract of polysaccharide from an edible brown algae Hijikia fusiforme also possess the ability to enhance the release of tumor necrosis factor-alpha from macrophages as proved in C3H/HeJ mice (201).

The anticancer potential of marine derived sulfated polysaccharides can be directly related to their other pharmacological responses like immunomodulation and antioxidant activity. In vitro and in vivo anticancer effect are greatly influenced by the increased production of immunomodulators like cytokines and nitric oxide and also by the activation of macrophages (43). The ROS scavenging ability of these compounds forms major basics of their anticancer activity. Several reports are available regarding the antioxidant and antiproliferative activity of the sulfated polysaccharides (94, 116).

Sulfated Polysaccharide Induced Cancer Arrest--In Literature and The Mechanism

Cancer is the second leading cause of global death after heart diseases (202). The common treatments for cancer include surgery, chemotherapy, radiotherapy, immunotherapy and also modern approaches like hormonal and gene therapy. These therapies have undesired side effects because the therapeutic agents are toxic not only to cancer cells but also for normal cells. Management of post therapy complications are also challenging (203). So finding novel, effective and nontoxic compounds from natural sources is the need of the hour. Similar to plants, the seaweeds are excellent source of vitamins, minerals, iodine and proteins, have shown promising activities against cancer. They also contain high amounts of polyphenols such as catechin, epicatechin, epigallocatechingallate, gallic acid, etc. which are also accountable for their anticancer activity (204).

The bioactive components in the extracts of marine red algae Gracilaria corticata 11. can inhibit the proliferation of Human leukemic cell lines. Induction of caspase-dependent apoptosis was elicited by Plocamium telfairiae on HT-29 colon cancer cells (181). The action of red algae Gracilaria tenuistipitata to inhibit the proliferation of Ca9-22 oral cancer cells is mediated by inducing DNA damage and apoptosis (205). The red algae Chondria atropurpurea showed cytotoxicity against human nasopharyngeal and colorectal cancer cells (206). The alcoholic extract of the red alga Acanthophora spicifera exhibits in vivo tumoricidal activity by increasing the mean survival time, decreasing tumor volume and viable cell count (207).

The green algae also possess significant anticancer resources. Capsosiphon fulvescens induced sarcoma-180 (a connective tissue tumor in mouse) growth inhibition activity (208). U. fasciata, a species of green algae, reduced the proliferation of HCT-116 human colon cancer cells to 50% at a concentration of 200i g/ml. The cells, upon treated with algal ethanolic extracts, have undergone morphological changes, apoptotic body formation, DNA fragmentation, cell cycle arrest in sub-G1 phase and mitochondrial membrane depolarization. These observations revealed that the algal extracts act by the induction of apoptosis. The gene expression studies confirmed modulation of Bax and Bcl-2 expression and activation of caspase-9 and caspase-3 (209).

The antiproliferative effect of heterofucans from brown algae Sargassum filipendula on cervical, prostate and liver cancer cells was well studied by Costa et al. (210). Laminaria japonica, a brown seaweed, was found to have anticancer effect when tested with human colon cancer cells (211). Fucoxanthin, carotenoid found in brown algae, inhibited the growth of LNCap prostate cancer cells in a dose-dependent manner. This effect is achieved by the induction of GADD45A expression and G(1) cell cycle arrest (212). The water extracts of brown alga Sargassum oligocystum have remarkable antitumor activity against K562 and Daudi cell lines at concentrations 5001 g/ml and 4001g/ml of the algal extract (213).

Several studies reported the anti proliferative effect of sulfated polysaccharides from marine algal sources. The antioxidant activity of sulfated polysaccharides accounts for their anticancer effects also. Sulfated polysaccharides from brown seaweeds Saccharina japonica and Undariapinnatifida distinctly inhibited proliferation and colony formation in both breast cancer and melanoma cell lines in a dose-dependent manner (214). The antiproliferative effects of heterofucans from marine algae Dictyopteris delicatula on HeLa cells attained saturation level at a concentration of 2mg/ml (94). Antiproliferative effects of five heterofucans isolated from Sargassum filipendula were performed with HeLa, PC3 and HepG2 cells using MTT test by Costa et al. All of them exhibited a dose dependent inhibition on the proliferation of tested cells and the strongest effect was observed for HeLa cells (210). Anionic polysaccharides from brown seaweed Sargassum vulgares showed an inhibitory effect on angiogenesis by inhibiting VEGF secretion in endothelial cells. The same polysaccharides exhibited antiproliferative effect on HeLa cells also (215).The effective concentration of sulfated polysaccharides for arresting HeLa cell proliferation was reported to be 0.01-2 mg/ml as studied from tropical seaweeds S. filipendula, D. delicatula, Caulerpa prolifera and Dictyota menstrualis (216).

Anionic polysaccharides SV1(Sargassum vulgare 1) and PSV1 (purified Sargassum vulgare 1) from brown seaweed Sargassum vulgare showed an inhibitory effect on angiogenesis in vivo in the chick chorio allantoic membrane (CAM). The result was also confirmed by the inhibition of tubulogenesis in rabbit aorta endothelial cell (RAEC) in matrigel (215). The sulfated polysaccharide isolated and fractionated from Sargassum plagiophyllum showed anticancer property against HepG2 and A549 cells with IC50 values of 600 [micro]g/ml and 700 pg/ml respectively while crude extract exhibited IC50 concentrations of 1200 and 1400 [micro]g/ml (50).

Fucoidan induced apoptosis on HT-29 and HCT-116 cells by activating the caspases 8, 9, 7, and 3, TRAIL, Fas and DR5 proteins (217). Fucoidan isolated from the sporophyll of cultured Korean brown seaweeds Undaria pinnatifida possessed tumoricidal activity which was proved in vitro using PC-3, HeLa, A549 and HepG2 cells (37). Crude fucoidan extracted from Sargassum species and Fucus vesiculosus was found to significantly decrease the viable number of Lewis lung carcinoma cells (LCC) and melanoma B16 cells (MC) cells in a dose-response fashion. The morphological changes of B16 cells proved fucoidan as an efficient antiproliferative agent. Flow cytometric analysis by Annexin V staining of the melanoma cells exposed to this polysaccharide confirmed the induction of apoptosis by the activation of caspase-3 (43). The anticancer activity of the fucoidan from the brown seaweed Undaria pinnatifida was investigated in human hepatocellular carcinoma SMMC-7721 cells also. Fucoidan cause the death of cells by the accumulation of high intracellular levels of reactive oxygen species (ROS) and associated depolarization of the mitochondrial membrane and caspase activation (164). Also, the fucoidan obtained from Undaria pinnatifida induced the apoptosis of PC-3 cells by activating both intrinsic and extrinsic pathways (217). It was also found that oral administration of fucoidan extracted from Cladosiphon okamuranus in a tumor (colon 26) bearing mouse model showed significant suppression of tumor growth and an increase in survival time (218).

The mechanism of anticancer activity of fucoidan on mouse breast cancer was studied in vitro and in vivo. The result showed significant decrease in the viability of 4T1 cells (mouse mammary carcinoma), induction of apoptosis and down-regulation of VEGF signaling. Similarly, intraperitoneal injection of fucoidan in breast cancer models reduced the tumor volume and weight (219). Moreover fucoidan reduced the viable cell number of MCF-7 cells by inducing inter nucleosomal DNA fragmentation, chromatin condensation, activation of caspases 7, 8, and 9 and cleavage of poly (ADP ribose) polymerase (220). The detailed mechanism of sulfated polysaccharides for anticancer activity is discussed in the following session.

In most of the cases sulfated polysaccharides showed a dose dependent anticancer effect. Increase in the concentration increase its activity also. The table 5 shows the anticancer potential of some sulfated polysaccharide and their effective concentration. Most of the authors reported IC50 values at higher concentrations (0.2 to 2mg/ml). The concentration dependence of the sulfated polysaccharides in eliciting anticancer activities, the active functional components involved and the functional mechanism underlying needs to be explored.

As most types of cancers are progressed by mal-regulation of apoptosis, the apoptotic pathways and cell cycle form an ideal target for cancer therapy 168.. Apoptosis is a highly regulated mechanism in multi-cellular organisms for normal growth and survival in either physiological or pathological conditions (225). Apoptosis is characterized by biochemical and morphological changes in the cell such as chromatin condensation, nuclear fragmentation, membrane blebbing, cytoskeletal rearrangement and cell shrinkage. The fate of apoptotic cells is phagocytosis by macrophages so as to prevent inflammatory responses (226). Apoptosis can be executed mainly by two pathways; extrinsic and intrinsic pathways. Both pathways are mediated by intracellular cysteine proteases called Caspases. The caspases are of two types--initiators and executioners. Apart from caspases certain growth factor mediated signaling pathways such as PI3K-Akt signal pathway, mitogen activated kinases (MAPKs) pathway are reported to involve in cellular proliferation, differentiation, and apoptosis (227).

Many novel anticancer therapies are targeting the apoptotic pathway, cell cycle progression and growth signal transduction within cancer cells. Taxol is a widely used anticancer drug from plants which can arrest cell cycle by interacting with microtubules (228). Vincristine and Vinblastine are another two widely used anticancer drugs of plant origin. Vincristine, the vinca alkaloid from the periwinkle Catharanthus roseus, also act by microtubule disassembly (229). A broad-spectrum protein kinase inhibitor, Staurosporine, an antibiotic from the bacterium Streptomyces staurosporeus, is reported to have the ability to release cytochrome c and results in caspase activation (230).

Marine niche also contributes much in the development of anticancer drugs and many of such marine derived compounds are in the pre-clinical stage. Cytarabine, Ara-C (Cytosar-U[R]) and Trabectedin or Ecteinascidin 743 (Yondelis[R]), are the anticancer drugs which are approved in European countries for use as antitumor drugs (121). A review on marine anticancer therapy by Jimeno et al; detailed the clinical status of ET-743 (Yondelis), AplidinR and Kahalalide F which are derived from marine organisms. Yondelis is a transcription inhibitor of tunicate origin and is in the third pre-clinical stage. AplidinR is, also from tunicate, translational inhibitor which is in the second phase of clinical studies. Kahalalide F is from green algae and is in the first stage of clinical development (231).

Polysaccharides especially sulfate containing ones are now under scientific research for the generation of new anticancer drugs due to their antiproliferative effects and compatibility. Kim et al reported that fucoidan induced apoptosis in HT-29 cells through the activation of the death receptor-mediated pathway. Fucoidan induced an increase in the levels of death receptors such as Fas, TRAIL, and DR5 proteins. The study also reported an increase in caspase-8 which is activated only in extrinsic death receptor pathway. Furthermore there was an increase in t-Bid and decrease in anti-apoptotic protein [Bcl.sub.2] on treatment with fucoidan (232). The sulfated polysaccharide from green algae Enteromorpha intestinalis induces apoptosis in HepG2 cells through caspases-mediated mitochondrial signaling pathway. The determination of the levels of decreased expression of Bcl-2 and an increase in Bax, cleaved caspase-3, cleaved caspase-9 and cytochrome c release confirmed their apoptotic potential (233). Sulfated polysaccharide of green algae Ulva fasciata also showed similar pattern of apoptosis in HCT 116 human colon cancer cells by modulating Bax and Bcl-2 expression (209).

A study by Xue et al using crude fucoidan revealed a reduction in the proliferation of mouse breast cancer 4T1 cells. The antiproliferative effect was elicited by stimulating apoptosis and decreased expression of VEGF, ERKs and Bcl-2 and increased release of cytochrome c and caspase-3 (219). Fucoidan from brown algae Undaria pinnatifida also induced apoptosis on A549 human lung carcinoma cells via caspases and MAPK mediated pathways. Also apoptosis was induced by the down regulation of p38, PI3K/Akt, and the activation of the ERK1/2 MAPK pathway (220, 222). The anticancer activity of heterofucan from brown algae Sargassum filipendula is elicited through decreased expression of Bcl-2 and increased expression of apoptogenic protein Bax (210). Fucoidan from Undaria pinnatifida displayed typical features of apoptotic cells when treated with human hepatocellular carcinoma SMMC-7721cells. Here a drastic decrease in the inhibitor of apoptotic protein and increase in the Bax to Bcl-2 ratio was evident (164). The action of fucoidan on cancer cell lines progressed in a dose dependent manner.

The ability of fucoidan in the phosphorylation of ERK without altering the phosphorylation status of p38 and Akt was studied in human lymphoma HS-Sultan cell lines by Asia et al. The increase in caspase-3 expression also supported the anticancer effects (234). Fucoidan from Fucus vesiculosus went on by another mechanism on HCT-15 cells, by the activation of ERK and p38 kinase and inactivation of PI3K/Akt pathway (235). Similarly fucoidan from Undaria pinnatifida showed activation of the ERK1/2 MAPK, and the inactivation of the p38 MAPK and PI3K/Akt signaling pathway in PC-3 human prostate cancer cells (217).

Sulfated polysaccharides also mediate the anticancer activity through the enhancement of host immune system. Enhanced production of various cytokines and NO by macrophages and natural killer cells on treatment with sulfated polysaccharides can account for their tumoricidal activity also (236). The sulfated polysaccharides from green seaweed Enteromorpha prolifera stimulated NO and various cytokine production from a macrophage cell line, Raw 264.7. Considerable increase in the mRNA expression of TNF a, IL-6, V and IL-10 was observed in the study by Kim et al; (194). Similar results were also obtained in another study using the green algae Capsosiphon fulvescens (193). The immunostimulation by fucoidan from Korean U. pinnatifida sporophyll was evident through the increased cytokines and chemokines production from macrophages and splenocytes. TNF a and IL-6 were found to be increased on treatment with fucoidan (237). In another study the antitumor activity of fucoidan against Lewis lung carcinoma and melanoma B16 cells was found to be mediated through enhancement of NK cell activity (43).

Fucoidan induced apoptosis was reported on several cell linesMCF-7, MDA-MB-231, HeLa, HT1080 and so on. Both the extrinsic and intrinsic pathways are operating and the cells displays typical apoptotic morphology (238). But we are lacking sufficient literature regarding the exact mechanism of action of these polysaccharides. Moreover the effect and involvement of the sulfate groups of fucoidan in the cancer prevention is still an enigma and needs to be studied in detail. The proposed mechanism of anticancer action of sulfated polysaccharides is depicted in Fig.6.

Conclusions and Future Directions

The cancer therapeutic approach using biological molecules is promising. Still management of side effects and associated complications are challenging. Poly anionic sulfated saccharides from marine algal origin offer several biological responses which can be exploited for the management of deformities of several tissues and organs. In the current article, such responses like antioxidant, antimicrobial, anticoagulants and antiinflammatory effects were taken into account. We also made an attempt to portrait the bioavailability and associated mechanism of sulfated polysaccharides in mammalian system. But this remains to be studied in detail.

Our main focus was to evaluate the anticancer potential of sulfated polysaccharides from marine algal source. Critical analysis of abundantly available literature revealed their potential to arrest the proliferation of several types of cancer cells in vitro. But the in vivo responses in higher animal models are not so promising. Moreover the concentration required for attaining IC50 values for cytotoxicity was higher (usually in mg) which was much higher when compared with the standard anticancer drugs. Furthermore the active components/functional groups responsible for these antiproliferative responses are yet to be revealed. The degradation product formation and their effect and clearance from the target site also needed to be studied in detail. Extensive research is wanting in these aspects for resolving such issues.

[FIGURE 6 OMITTED]

The site directed targeting and target specific binding of sulfated polysaccharides towards cancer tissues or cells were not studied yet. The possibility of sulfated polysaccharides in preventing cancer metastasis also needed to be studied. The fate of sulfated polysaccharides at the cancer site is also debating. We are lacking sufficient literature regarding the influence of acidic pH surrounding the cancer tissue on the structural integrity of sulfated polysaccharides. In addition to this, the implications for chances of electrostatic repulsions occurring between negative charged sulfated polysaccharides and that of cancer cell surface still remain unattempted.

The ROS scavenging effects, antimicrobial effects, immunomodulatory and anti-inflammatory effects of sulfated polysaccharides are the added advantages when anticancer effects are concerned. Because these properties can be exploited for taming the hostile environment of cancer where the ROS concentration is higher, chance of infection post and prior treatment is greater and immune invasion is prominent. In short the cumulative effects of these properties (discussed in the text) are beneficial for cancer management.

Since unregulated apoptosis forms the main player in carcinogenesis and cancer progression, most anticancer drugs target signaling pathways that ultimately end in apoptotic pathways. The down regulation of Bcl2 and p13K/AKT signals and up regulation of p38 and ERK has been reported to be involved in cancer cell arrest upon treatment with sulfated polysaccharides. But the actual mechanism behind this is unknown. The sulfated polysaccharides can act primarily on cancer cells either through direct interactions or it can activate or stimulate other signaling molecules which in turn can open the apoptotic pathways. These two possibilities are debatable and sufficient literatures regarding this aspect is still limiting. Moreover the involvement of secondary degradation products of sulfated polysaccharides in cancer prevention is another possibility to be explored.

Extensive research outcomes are required to answer these questions. The long array of evidences suggests that the sulfated polysaccharides are able to execute an anticancer effect. Its compatibility is promising too. Sulfated polysaccharides can be a potent candidate for the management of cancer either as an anticancer supplement or cancer therapeutic. But these investigations are only at preliminary level and are not sufficient. More studies are recommended at cellular and molecular level to extent these approaches to cancer therapeutic arena.

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Geena Mariya Jose, Muraleedhara Kurup G. *

Department of Biochemistry, University of Kerala, Karyavattom, Thiruvananthapuram, Kerala, India

Received U December 2014; Accepted 7 January 2015; Available online 2 February 2015

# Coresponding author: Dr. Muraleedhara Kurup G. Email :gmkbio@gmail.com
Table 1: Examples of Marine Macroalgae

PHYLUM         GENUS          COMMON NAME               EXAMPLE

Phaeophyta:    Alaria         Kelp, bladderlocks        Alaria
                                                          esculenta
               Ascophyllum    Egg wrack                 Ascophyllum
                                                          nodosum
               Ecklonia       Kelp                      Ecklonia
                                                          maxima
Phaeophyta:    Laminaria sp.  Kelp, kombu, sea tangle   Laminaria
                                                          digitata
               Himanthalia    Sea spaghetti, fucales    Himanthalia
                                                          elongate
               Fucus          Bladder wrack, rockweed   Fucus
                                                          vesiculosus
               Sargassum      Mojaban, Indian           Sarga ssum
                                brown seaweed/Sea         wightii
               Undaria        holly wakame              Undaria
                                                          pinnatifida
               Chondrus       Irish moss/carrageen      Chondrus
                                                          crispus
               Porphyra       Nori/ haidai/kim/gim      Porphyra
                                                          leuco sticte
               Gracilaria     Ceylon mos s,             Gracilaria
                                Chinese moss, Sea         gracilis
                              string, Sewing thread,
                              Dulse
Rhodophyta     Palmaria       Hedgehog seaweed          Palmaria
                                                          palmate
               Notogenia      Ahnfelt's seaweed         Notogenia
                                                          stiriata
               Ahnfeltia      Red sea fan               Ahnfeltia
                                                          plicata
               Callophyllis   Pottery seaweed           Callophyllis
                                                          Edentate
               Ceramium       Hidden rib                Ceramium
                                                          paeificum
               Cryptopleura   Sea bru sh                Cryptopleur
                                                          a ramo se
               Odonthalia     Goat tang                 Odonthalia
                                                          floccose
               Polyides       Polly Collins, Polly      Polyides
                                Hendry, Polly             caprinus
               Polysiphonia   Pacific, Lobster horns    Polysiphonia
                                                          lanosa
Chlorophyta:   Ulvaria        Laver/sea lettuce/        Ulva lactuca
                                sea grass/nori
               Chaetomorpha   Hog's bristle             Chaetomorpha
                                                          melagonium
               Cladophora     Green ball                Cladophora
                                                          trichotoma
               Enteromorpha   Silk confetti, Green      Enteromorpha
                                confetti, Link            intestinalis
                              confetti

Table 2: Composition of Certain Marine Macroalgae

Algal species         vitamins    elements             pigments

Cladophora
fascicularis,                                          chlorophyll a,
Sargassum                                              Chl b,
Polycustum,                                            Carotenoid
P. gymnospora
Gracilaria                        Ca, Mg, K, Na, Fe,
  salicornia,
Ulva lactuca                      Cu, Zn, Cl, Co, Ni

Enteromorpha
intestinalis,
Ceramium rubrum

                                                       Violaxanthin,
G. birdia e,                                           [beta]-
                                                         carotene,
G. domingensis                                         zeaxanthin,
                                                       aloxanthin
Gracilaria changgi,   Vitamin C

G. fisheri                        Ca, Mg, K, Na, Fe,
G. tenuisti pitata                Cu, Zn, Cl

Algal species         Volatile                References
                      compounds

C ladophora
fascicularis,
Sargassum                                     (J.I. et al. 2010)
Polycustum,
P. gymnospora
Gracilaria                                    (Tabarsaet al.
  salicornia,
Ulva lactuca                                  2012)
                      Tri chlorome thane,
Enteromorpha          Ace tone, 2 ethyl
intestinalis,         furan, octane,
Ceramium rubrum       pentanal, hexanal,      (Moore 1977)
                      hepatanl , octanal,
                      nonanal,

G. birdia e,                                  (Guaratini et al.
G. domingensis                                2012)

Gracilaria changgi,                           (Norziah and Ching
                                              2000)
G. fis heri                                   (Ommee Benjama
G. tenuisti pitata                            2012)

Table 3: Major antioxidant compounds in marine macroalgae (Monsnang
Yangthong et al; 2009) (115).

Sl/No   Compounds         Examples               Sources

                          [beta]-carotene
                          Fucoxanthin            Chondrus crispu s
                          Antheraxanthin,        Mastocarpus stellatus
1       Carotenoids       Lutein,                Brown algae
                          Violaxanthin,          Red algae
                          Xanthophylls
                          Zeaxanthin
                          Catechin,
                          Epicatechin
                          Gallate                Taonia atomaria
                          Fl avonoid s           Cystoseira species
2       Phenols           Ph lorotannins         Palmaria palmata
                          Stypodiol              Sargassum pallidum
                          Isoepitaondiol         Fucus vesicu losus
                          Taond iol
                          Terpe noids
3       Pigments          Phycoerythrin          Red algae
                          Phycocyanin
                                                 Chondrus crispu s
4       Vitamins          Ascorbate              Mastocarpus stellatus
                          Vitamin A              Sargassumsp.
                                                 Kappaphycus alvarezii
                          Fucoidan,
                          Algini c acid
                          Laminaran              Turbinaria conoides
5       Sulphated         Fucoidan               Laminaria japonica
        polysaccharides   Su lphat edgalactans   Red algae
                          Galactans              Sargassum wightii
                          Glyc os ami noglycan   Porphyra species
                          Porphyran

Table 4: Major antimicribial compounds of marine algal origin

no   Compound                  Nature               Activity
     Cycloeudesmol             Sesquiterpene        Antibacterial

     Halitunal                 Diterpene            Antiviral
                               Aldehyde
     N-palmitoyl-2-amino
     1,3,4,5-                  Sphingosin           Antiviral
     tetyrahydroxyoctadecane
     Capisterones A and B      Triterpene           Antifungal
                               Sulphate esters
     Caulerpals A and B        Sesquiterpenes       Antifungal

     Nigricanosides            Glycoglycerolipids   Antifungal
     A and B
     (6R)-6-hydroxy
     dichototomo 3,14-diene-   Diterpene            Antiviral
     1,17-dial
     8,8'-bieckol              Phlorotannin         Antiviral

     Meth oxybifurcaren one    Meroditerpenoid      Antifungal

     Peyssonol A and B         Sesquiterpene        Anti viral
                               hydroquinone
     Elatol                    Halogenated          Anti
                               sesquiterepene       bacterial
                               alcohol
                                                    Antibacterial
     Callophycols              Diterpenebenzoic     ,antimalarial,
     A and B                   acids                and
                                                    antifungal
                                                    activity

no   Compound                  Nature               Source
     Cycloeudesmol             Sesquiterpene        Chondria
                                                    oppositi cla da
     Halitunal                 Diterpene            Halimeda
                               Aldehyde             Tuna.
     N-palmitoyl-2-amino
     1,3,4,5-                  Sphingosin           Ulva fasciata.
     tetyrahydroxyoctadecane
     Capisterones A and B      Triterpene           Panicillus
                               Sulphate esters      Capitatus
     Caulerpals A and B        Sesquiterpenes       Caulerpataxifolia

     Nigricanosides            Glycoglycerolipids   Avrainvillea
     A and B                                        nigrans
     (6R)-6-hydroxy
     dichototomo 3,14-diene-   Diterpene            D. Menstrual is
     1,17-dial
     8,8'-bieckol              Phlorotannin         Ecklonia
                                                    Cava,
     Meth oxybifurcaren one    Meroditerpenoid      Cystoseiratamaris
                                                    cifolia
     Peyssonol A and B         Sesquiterpene        Peyssonnelia
                               hydroquinone         species
     Elatol                    Halogenated          L. Elata
                               sesquiterepene
                               alcohol

     Callophycols              Diterpenebenzoic     Callophycus
     A and B                   acids                Serratus

no   Compound                  Nature               Reference
     Cycloeudesmol             Sesquiterpene        Ali and Gamal
                                                    (2010)123.
     Halitunal                 Diterpene            Koehn et al.
                               Aldehyde             (1991) 124.
     N-palmitoyl-2-amino
     1,3,4,5-                  Sphingosin           Garg et al. 1992
     tetyrahydroxyoctadecane
     Capisterones A and B      Triterpene           Puglisi
                               Sulphate esters      et al. (2004) 125.
     Caulerpals A and B        Sesquiterpenes       Aguilar-Santos
                                                    (1970)126.
     Nigricanosides            Glycoglycerolipids   Williams
     A and B                                        et al. (2007) 127.
     (6R)-6-hydroxy
     dichototomo 3,14-diene-   Diterpene            Pereira et al.
     1,17-dial                                      (2004) 128.
     8,8'-bieckol              Phlorotannin         Fukuyama
                                                    et al. (1989) 129.
     Meth oxybifurcaren one    Meroditerpenoid      Bennam ara et al.
                                                    (1999)130.
     Peyssonol A and B         Sesquiterpene        Talpir et al.
                               hydroquinone         (1994)131.
     Elatol                    Halogenated          Sims (1974) 132.
                               sesquiterepene
                               alcohol
     Callophycols              Diterpenebenzoic     Lane et al. (2007)
     A and B                   acids                133.

Table 5: The anticancer potential of some sulfated polysaccharide and
their effective concentration

Algal source       Cell line   Effective
                   used        concentration

Sargassum          HepG2       600 [micro]g/mL
  plagiophyllum    A549        700 [micro]g/mL
Ulva fasciata      HCT 116     200 [micro]g/mL

Undaria            PC-3        200 [micro]g/mL,
  pinnatifida
S.filamentosa      DU-145      100 [micro]g/mL
                   MCF-7       100 [micro]g/mL

C. mediterrranea   MCF-7       100 [micro]g/mL

U. pinnatifida     T-47D       200 [micro]g/mL.
                   SK-MEL-28   200 [micro]g/mL
Undaria            A549        200 [micro]g/mL,
  pinnatifida
Cladosi phon       Huh7        2.0 mg/ml
okamuranus
                   HepG2       4.0 mg/ml
S. pallidu m       A549        1.000 mg/ml

Algal source       %            Reference
                   decreasein
                   viability

Sargassum          50%          Suresh et al. (2013)
  plagiophyllum    50%          50
Ulva fasciata      50%          Ryu et al. (2013)
                                2 09.
Undaria            45.1%        Boo et al. (2013)
  pinnatifida                   217.
S.filamentosa      90%          Taskin et al. (2010)
                   80%
                                221.
C. mediterrranea   55%          Taskin et al. (2010)
                                221.
U. pinnatifida     46%          Vishchuk et al.
                   34%          (2011) 214.
Undaria            52.1%        Boo et al. (2011)
  pinnatifida                   2 22.
Cladosi phon       50%          Nagamine et al.
okamuranus
                   50%          (2009) 223.
S. pallidu m       50%          Ye et al. (2008)
                                224.
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Author:Jose, Geena Mariya; G., Muraleedhara Kurup
Publication:Trends in Biomaterials and Artificial Organs
Date:Jan 1, 2015
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