Anticancer agents derived from marine algae

9 Anticancer agents derived from marine algae N. Sithranga Boopathy and K. Kathiresan, Annamalai University, India

DOI: 10.1533/9780857098689.2.307 Abstract: Cancer is one of the most dreadful human diseases and it has a multiple etiology, including lifestyle, culture and environment. Despite there being many synthetic anticancer drugs available in the market, there remains a need for potent drugs of natural origin. In this regard, marine algae, which are rich in phytochemicals and show a wide species diversity, are a promising source. Information is available on the health benefits of marine algae as both preventive and curative agents for ailments. However, marine algae-derived compounds have not as yet entered post-clinical trials. The present review consolidates the available information on marine algae-derived anticancer principles and their possible mode of action. Key words: marine algae, seaweeds, anticancer activity, immunomodulation, apoptosis.

9.1

Introduction

Cancer is a dreadful human disease with uncontrolled growth and spread of abnormal cells. It is caused by external factors (tobacco, infectious organisms, poor nutrition, chemical agents and radiation) and internal factors (inherited mutations). The cancers caused by external factors such as tobacco and infectious organisms are preventable by means of early detection and removal of precancerous lesions (American Cancer Society and Surveillance, 2006). Cancers represent the largest cause of mortality in the world and claim over six million deaths annually (Rajesh Dikshit, et al., 2012). The number of cancer deaths is projected to increase with population growth and increasing life expectancy (Jha, 2009). The incidence of

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308 Functional ingredients from algae for foods and nutraceuticals cancers continues to increase in magnitude with climate change and global warming, as has also been experimentally proved (Kathiresan and Sithranga Boopathy, 2008). Tobacco use is the most important etiology for cancer, causing 22% of global cancer deaths including 71% of lung cancer deaths. Cancer-causing viral infections such as HBV/HCV and HPV are responsible for up to 20% of cancer deaths in developing countries. Lung, stomach, liver, colon and breast cancers cause rapid cancer deaths each year and global cancer deaths are projected to continue rising, with an estimated 13.1 million deaths in 2030 (WHO, 2012). There is a dire need to find a potent, safer and cheaper drug to cure these cancers. In this regard, algae, in particular marine algae, are rich in bioactive compounds that may act as antioxidant, antimicrobial, antiviral, antiinflammatory, antitumour, anticoagulant and hypocholesterolemic agents (Frestedt et al., 2009; MacArtain et al., 2007; Matsui et al., 2003; Tannin-Spitz et al., 2005; Wu et al., 2005). Marine algae have been used for medicinal purposes since the 17th century because of their phytochemical constituents and high species diversity. Marine algae are classified as phytoplankton (microalgae) and seaweed (macroalgae). There are more than 5000 different species of phytoplankton and 6000 species of macroalgae (seaweeds). Phytoplankton comprise organisms such as diatoms (Bacillariophyta), dinoflagellates (Dinophyta), green and yellow-brown flagellates (Chlorophyta, Prasinophyta, Prymnesiophyta, Cryptophyta, Chrysophyta and Rhaphidiophyta) and blue-green algae (Cyanophyta). The seaweeds belonging to Rhodophyta, Phaeophyta and Chlorophyta are commonly known as red, brown, and green seaweeds respectively (Ravikumar and Kathiresan, 1993). This review is aimed at analyzing the work so far carried out on anticancer activity of marine algal extracts.

9.2

Anticancer potential of marine algae

Many studies have focused on water soluble antitumour active substances from marine algae; however, most anticancer agents have not been used clinically because of their undesirable side effects on normal cells (Harada et al., 1997). The bioactive substances either kill cancer cells by inducing apoptotic death, or affect cell signaling through activation of the members of protein kinase-c family of signaling enzymes (Sithranga Boopathy and Kathiresan, 2010). Marine algae produce an array of anticancer phytochemicals, and the important ones are shown in Table 9.1 and Figs. 9.1a–9.1c. 9.2.1 Cyanophyceae Cyanobacteria in general and marine forms in particular are rich sources of novel bioactive compounds (including toxins) for pharmaceutical applications.

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Table 9.1

Anticancer compounds derived from marine algae

Source

Compound

Activity

Type studies Reference

Cyanobacteria Stigonema sp.

Scytonemin

Protein serine/threonine kinase inhibitor, antiproliferative Possible use in cancer therapy to treat bone cancer Potent cytotoxic cyclic depsipeptides Anticancer

In vitro

Stevenson et al., 2002a,b

In vitro

Mahdi and Fariba, 2012

In vitro

Tripathi et al., 2012

In vitro In vitro In vitro

Rickards et al., 1999; Koehn et al., 1992 Moore, 1978 Rickards et al., 1999

In vitro In vitro

Koehn et al., 1992 Carte, 1996

In vitro

Banker and Carmeli, 1998; Davidson, 1995

Cyanotoxins © Woodhead Publishing Limited, 2013

Lyngbya majuscule

Anatoxin-A microcystins/ nodularin Lagunamides A (1) and B (2)

Calothrix sp.

Calothrixin

Aphanizomenon flosaquae Calothrix sp.

Aphanorphine, Siatoxin Crude extract

Lyngbya majuscula Lyngbya majuscula

Microcolin-A Curacin-A

Nostoc linckia and N. Borophycin spongiaeforme var. tenue lines Dinophyceae Poterioochromonas mathumensis Procentrum belizeanum

Malhamenicilipin-A 19–epi-Okadaic acid

Anticancer Inhibits the growth of human HeLa cancer cells in a dosedependent manner Immunomodulator Antiproliferative agent, it inhibits the polymerization of the tubulin Cytotoxicity against human epidermoid carcinoma and colorectal adenocarcinoma cells

Inhibits the protein tyrosine kinase In vitro (PTK) A new protein phosphatase In vitro inhibitor

Chen et al., 1994 Cruz et al., 2007; Paz et al., 2008 (Continued )

Table 9.1

Continued

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Source

Compound

Activity

Type studies Reference

Species of Procentrum: P. acuminate, P. arenarium, P. belizeanum, P. concavum, P. fortii and P. maculosum Peridinium bipes Dinochrome A

Okadaic acid

The in vivo toxicity is highly toxic against leukaemia cells by inhibiting the enzymes of protein phosphatase 1 and 2A

In vitro

Dinochromes A and B

Antiproliferative active against the human tumour cells, such as GOTO (Neuroblastoma) OST (Osteosarcoma) and HeLa (Cervical cancer). Cytotoxicity for human lung cancer cell lines (A-549) and HL (human myeloblastic leukaemia) Cytotoxic, antitumour and antineoplastic Strong immunostimulator In vivo

Amphidinium sp.

Lingshioils A

Amphidinium sp.

Amphidinolid

Gyrodinium impudicaum

Sulphated polysaccharide

Chlorophyceae Enteromorpha prolifera

Pheophytin Crude extract

Ankistrodesmus gracilis and Amphyprora alata Caulerpa microphysa

Crude extract

Ulva fasciata

Crude extract

Suppressive effect against chemically induced mouse skin tumorigenesis Exhibit strongest inhibition to KB cells Anticancer against leukaemia cells (HL-60) (BCRC 60027) and BALB/c mice with transplanted myelomonocytic leukaemia Dalton’s ascitic lymphoma (DAL) cells in Swiss albino mice.

Takai et al., 1987; Walker and Watson, 1992

Huang et al., 2004a, b

Washida et al., 2006 Yim et al., 2003; 2005 Yim et al., 2003; 2005 Okai et al., 1996a

In vitro

Hoa et al., 2011

In vitro

Hui et al., 2012

In vivo

Abirami and Kowsalya, 2012

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Source

Compound

Activity

Type studies Reference

Chlorella vulgaris

Immunomodulators

In vivo

Burtin, 2003

Cladophora fascicularis

Oleic acid, palmitic acid, linolenic acid, γ-linolenic acid, docosahexaenoic acid (DHA) Porphyrinolactone

In vitro

Huang et al., 2007

Avrainvillea nigricans

Nigriccanoides A and B

In vitro

Williams et al., 2007

Cymopolia barbata and Neomeris annulata Cymodocea nodosa

In vitro

Gerwick, 1997

In vitro

Konitza et al., 2005

Bryopsis sp.

Cymobarbatol and 4-isocymobarbatol Some diaryl heptanoides such as cymodienol, cymodiene, isocymodine and nodosal Kahalaides

Inhibitory activity of NF-kB which is the origin of TNFα (Tumour necrosis factor) group of cytokines Antimitotic activity for human breast cancer (MCF-7) Potent antimitogenic properties

In vitro

Konitza et al., 2008

Caulerpa sp.

Caulerpenyne

In vivo

Cystophora sp.

Meroterpenes and usneoidone

Urones et al.,1992; Fischel et al., 1995 Parent-Massin et al., 1996; Barbier et al., 2001

Cytotoxic for the cell line NSCLC-N6 of non-small cell lung cancer cell Phase II of clinical trials for its actions on breast and prostate tumours and also it causes entered disruption of the membrane of lysosomes causing cell death Anticancer, antitumour, and antiproliferating properties Antitumour property

In vitro and In vivo

(Continued )

Table 9.1

Continued

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Source

Compound

Activity

Enteromorpha prolifera

Pheophytin

Potent suppressive effect against chemically induced mouse skin tumorigenesis through suppression at initiation and promotional phases

Okai et al., 1996a

Fucoidans

Inhibiting tumour metastasis in the rat mammary adenocarcinoma cells (13762 MAT) Inhibits the invasion of human breast cancer cells Inhibits the invasion of colon adenocarcinoma cells (AGS) and HT-29 colon cancer In vivo and cells and mammary tumours in vitro

Zhuang et al., 1995; Coombe et al., 1987; Haroun-Bouhedja et al., 2002

Phaeophyceae Sargassum thunbergii Fucus vesiculosus Ascophyllum nodosum

Laminaria japonica, Porphyra tenera, Gelidium amansii and Euchema cottonii Saccharina japonica and Undaria pinnatifida Halimeda stuposa Dictyota sp.

Crude extracts

Sulphated polysaccharides

Type studies Reference

Antitumour activity against In vitro human breast cancer T-47D and melanoma SK-MEL-28 cell lines 4-hydroxydictyolactone (1), and Cytotoxic activities against human In vitro the diterpenes dictyol E (2), and mammalian cell lines SF8,11-dihydroxypachydictyol 268, MCF-7, H460, HT-29 and A (3) and indole-3CHO-K1. carboxaldehyde (4)

Funahashi et al., 2001; Namvar et al., 2012 Olesya et al., 2012 Simon et al., 2012

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Source

Compound

Activity

Stipodium zonales

Stypoquinoic acid, demathoxyatomaric acid

Sargassum oligocystum

Water extract

Ascophyllum sp.

Sulphated fucan, ascophyllan

Fucus evanescens

Fucoidans

Inhibitor of tyrosine kinase and cytotoxic towards lung and colon cancers Anticancer activity against human In vitro Daudi and K562 cancer cell line Cytotoxicity against various cell In vitro lines MDCK, Vero, PtK1, CHO, HeLa, and XC Antitumour and antimetastatic In vivo activities

Chondria sp.

Condriamide-A

Saccharina japonica and U. pinnatifida

Fucoidans

Eisenia bicyclis

Phloroglucinol and its polymers, namely, eckol (a trimer), phlorofucofuroeckol A (a pentamer), dieckol, and 8,8’-bieckol (hexamers)

Rhodophyceae Acanthospora spicifera

Crude

P. tenata

Crude

Cytotoxicity towards human nasopharyngeal and colorectal cancer cells Inhibit proliferation and colony formation in both breast cancer and melanoma cell lines in a dose-dependent manner Anticancer activity

Exhibits tumouricidal activity against Ehrlich’s ascites carcinoma cells (EAC) Reduce intestinal tumor incidence in rats

Type studies Reference Dorta et al., 2002, 2003 Zandi et al., 2010 Jiang et al., 2010

In vitro

Alekseyenko et al., 2007; Wijesinghe and Jeon, 2012 Palermo et al., 1992

In vitro

Olesya et al., 2011

In vitro

Nakamura et al., 1996; Shibata et al., 2002; Sithranga Boopathy and Kathiresan, 2010

In vitro

Vasanthi et al., 2004

In vivo

Yamamoto et al., 1986 (Continued )

Table 9.1

Continued

Source

Compound

Activity

Type studies Reference

Chondrus ocellatus

λ- Carrageenans

Immunostimulant antitumour activity

In vivo

Porteria hornemannii

Halomon

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Porteria hornemannii Gracillaria asiatica Laurencia filiformis Laurencia obtusa

Strong cytotoxic action against several cancer cell lines (brain, kidney and colon) A monoterpenes along with Acts as DNA methyl tranferase halomon inhibitors Gracilarioside and gracilamides Strong cytotoxicity for the A375– A and B 52 human melanoma cell line Preparguerene Cytotoxicity on several cell lines (B16, HeLa, and P388) Teurilene Cytotoxicity

In vitro In vitro In vitro In vitro In vitro

Yamada et al., 1997; Zhou et al., 2004, 2005, 2006 Fuller et al., 1994; Sotokawa et al., 2000 Andrianasola et al., 2006 Sun et al., 2006 Suzuki et al., 1989; Takeda et al., 1990 Suzuki et al., 1985

Anticancer agents derived from marine algae 315 (a)

O

H O O

O O H

O

N

H N

O CI

H

H

O

H

Alpha linoleic acid (CID 5280450) + H

O

Cryptopycin 1 and 8 (CID 6438401)

N

H

N

H O-

H

H O

H

N

H

H H

O-

O

O

H H

H

H

N H

O

H H

H

H H

O

O H

H

N+ N

Cyclic peptide (CID 5458539)

Docosahexaenoic acid (CID 445580)

Fig. 9.1 (a–c) Some anticancer compounds derived from marine algae. (CID refers to the chemical index database numbers.)

Cyanobacteria produce cyanotoxins such as anatoxin-A and microcystins/ nodularin which have the potential to treat bone cancer (Mahdi and Fariba, 2012). Lagunamides A (1) and B (2) are potent cytotoxic cyclic depsipeptides isolated from the filamentous marine cyanobacterium, Lyngbya majuscula, and are structurally related to the aurilide-class of molecules, which have been reported to possess potent anti-proliferative activities against cancer cells. Anticancer efficacy of Nostoc muscorum and Oscillatoria sp. extracts is reported as inhibiting the Ehrlich’s Ascites Carcinoma Cell (EACC) and Human Hepatocellular cancer cell line (HepG2) (Tripathi et al., 2012). Scytonemin, isolated from Stigonema sp., is a protein serine/threonine kinase inhibitor (Stevenson et al., 2002a). The scytonemin is a yellow-green ultraviolet sunscreen pigment present in the extracellular sheaths of different genera of aquatic and terrestrial blue-green algae. Scytonemin regulates mitotic spindle formation as well as enzyme kinesis involved in cell cycle control. Furthermore, the compound inhibits proliferation of human fibroblasts

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(b) H O

O

H

H

O O

H

H

H H

H

Linoleic acid (CID 5280933)

Lauric acid (CID 3893)

NH

N H

H N

N

HO

O

H

H

H

O

H O O O

H

H

H

O

Oleic acid (CID 445639)

Pheophytin (CID 5351507)

(c)

H O

O O H O

O

N H

N OO

O

N H H H N

H

O

O O

O

N

O

O

H

H O

Phloroglucin (CID 359)

Dideminins (CID 123844)

O O H O H

O

O

O

O

O O

O

O

O O H

O H

N

O

O-

H

Oscillatoxin (CID 46173825)

Hapalosin (CID 133055)

Fig. 9.1 Continued

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H N

Anticancer agents derived from marine algae 317 and endothelial cells. Thus, scytonemin may provide an excellent drug, as protein kinase inhibitors do have antiproliferative and anti-inflammatory activities (Stevenson et al., 2002b). Some of the marine cyanobacteria appear to be potential sources for large-scale production of vitamin E and B complex (Gustafson et al., 1989). The cell extracts of Calothrix isolates inhibit the growth in vitro of a chloroquine-resistant strain of the malarial parasite, Plasmodium falciparum and the human HeLa cancer cells in a dose-dependent manner (Rickards et al., 1999). Fractionation of the extracts followed by bioassay has led to their isolation and structure characterization of calothrixin A (I) and B (II), pentacyclic metabolites with an indole (3,2-j) phenanthridine alkaloids which exert growth inhibitory effects at nanomolar concentrations. An immunosuppressive linear peptide microcolin-A, isolated from L. majuscula, suppresses the two-way murine mixed lymphocyte reaction at nanomolar concentrations (Koehn et al., 1992). Another compound, curacin-A, isolated from L. majuscula is an exceptionally potent antiproliferative agent as it inhibits the polymerization of the tubulin, and the compound shows selectivity for colon, renal and breast cancer-derived cell lines (Carte, 1996). The most significant discoveries are of borophycin, cryptophycins 1 and 8, and cyanovirin. Borophycin is a boron-containing metabolite, isolated from marine cyanobacterial strains of Nostoc linckia and N. spongiaeforme var. tenue (Banker and Carmeli, 1999). The compound exhibits potent cytotoxicity against human epidermoid carcinoma and human colorectal adenocarcinoma cell lines (Davidson, 1995). Ankistrodesmus gracilis and Amphyprora alata exhibit the strongest inhibition to KB cells (Hoa et al., 2011).

9.2.2 Dinophyceae Many dinoflagellates can produce toxins. Some of these toxins are extremely powerful and many of them are effective at far lower dosages than conventional chemical agents (García et al., 2007). Malhamenicilipin-A isolated from Poterioochromonas mathumensis effectively inhibits protein tyrosine kinase (PTK) (Chen et al., 1994). It is exciting to note that many algae can convert simple fatty acids like arachidonic acids into complex eicosanoids and related oxylipins. Derivatives of arachidonic acids are important in maintaining homeostasis in mammalian systems to cure diseases such as psoriasis, asthma, arteriosclerosis, heart disease, ulcers and cancer (Carte, 1996). Okadaic acid is known to be present in many species of Procentrum: P. acuminate, P. arenarium, P. belizeanum, P. concavum, P. fortii and P. maculosum. Okadaic acid is of average toxicity; however, it is highly toxic against leukaemia through inhibition of protein phosphatase (Takai et al., 1987; Walker and Watson, 1992). 19–epi-Okadaic acid isolated from P. belizeanum is a new protein phosphatase inhibitor (Cruz et al., 2007; Paz et al., 2008). Dinochromes A and B are carotenoids isolated from the freshwater species Peridinium bipes. Dinochrome A shows effective antiproliferative activity

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318 Functional ingredients from algae for foods and nutraceuticals against the human tumour cell lines, such as GOTO (neuroblastoma), OST (osteosarcoma) and HeLa (cervical cancer). The lingshi oils A, isolated from Amphidinium sp., displays a strong cytotoxicity for human lung cancer cell line A-549 and human myeloblastic leukaemia cell line (HL) (Huang et al., 2004a, b; Washida et al., 2006). Another compound, amphidinolide, is derived from Amphidinium sp., exhibiting cytotoxic, antitumour and antineoplastic activities through deterioration of the DNA, as a result of alkylation from an intercalation by the actions of topoisomerases. The sulphated polysaccharide of Gyrodinium impudicum is a strong immunostimulator as proved in vivo against inflammation in a mouse model. The poly-β-D-galactan, sulphated in the 2nd position and esterified in the 3rd position by (+) L-lactic acid is an inhibitor of topoisomerases I and II (Yim et al., 2003, 2005).

9.2.3 Chlorophyceae Human promyelocytic leukaemia cells (HL-60, BCRC 60027) and BALB/c mice with transplanted myelomonocytic leukaemia are effectively controlled by enzyme extraction of Caulerpa microphysa extracts. The study concludes that the addition of C. microphysa-pepsin-digested extracts to HL-60 and WEHI-3 cell lines increase the DNA damage as compared to control (Hui et al., 2012). Abirami and Kowsalya (2012) have reported that the crude extract of Ulva fasciata shows tremendous anticancer activity against implanted Dalton’s ascitic lymphoma (DAL) cells in Swiss albino mice. The extracts significantly decrease cancer cell count, and consequently increase the lifespan of the treated mice. The haematological and biochemical alterations have been observed significantly in cancer-bearing animals due to the treatment with U. fasciata extracts. Nigriccanoides A and B isolated from Avrinvillea nigricans have potent antimitotic activity for human breast cancer (MCF-7) (Williams et al., 2007). Cymobarbatol and 4-isocymobarbatol isolated from two calcified species, Cymopolia barbata and Neomeris annulata, have potent antimitogenic properties (Gerwick, 1997). Kahalalide, a family of linear peptides and cyclic peptides, accumulates in the molluscan species Elysiya rufenscens by consuming the seaweed Bryopsis sp. Kahalalide has entered phase II of clinical trials for its actions on breast and prostate tumours and it also causes disruption of the membrane of lysosomes causing cell death. Some diarylheptanoids, such as cymodienol, cymodiene, isocymodine and nodosal, are isolated from the Cymodocea nodosa, along with a new brominated tricyclic diterpene (Konitza et al., 2008) and all these compounds are effectively cytotoxic for the cell line NSCLC-N6 of lung cancer (Konitza et al., 2005). Caulerpenyne from a green alga Caulerpa sp. shows its bioactivity against human cell lines and it exhibits anticancer, antitumour and antiproliferating properties. Two compounds, meroterpenes and usneoidone isolated from Cystophora sp., display antitumour properties (Barbier et al., 2001; Fischel et al., 1995; Parent-Massin et al., 1996; Urones et al., 1992). Pheophytin is a chlorophyll-related compound, isolated from

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Anticancer agents derived from marine algae 319 an edible green alga Enteromorpha prolifera, and the compound has a potent suppressive effect against chemically induced mouse skin tumourigenesis (Okai et al., 1996a). Chlorophyll-a and chlorophyll-b have significant suppression against the induction of ornithine decarboxylase in mouse skin fibroblasts caused by a tumour promoter, as proved by in vitro cell culture experiments (Okai et al., 1996b). Despite the abundance and availability of green seaweeds, relatively few studies have been performed on the molecular structures and bioactivities of their sulphated polysaccharides. In addition, there is little information available on the structures and anticancer and immunomodulatory activities. Capsosiphon fulvescens, a green alga, has been traditionally used in Korea as a functional food for centuries. A sulphated polysaccharide (SPS-CF) from C. fulvescens shows potent immunostimulating effects on murine RAW264.7 cells. The sulphated SPS-CF is able to activate macrophages to produce proinflammatory mediators, TNF-α, IL-6, NO and PGE2, suggesting its potential use as an immunomodulatory agent, taken together with the previously reported anti-gastric cancer activity (Kwon and Nam, 2007). In animal studies, extracts from Chlorella vulgaris display antitumour effects (Hasegawa et al., 2000). The C. vulgaris extract has also been found to induce apoptosis and oxidative damage in HepG2 cells (Saad et al., 2006). Therefore, microalgal species, such as C. vulgaris, can have the potential for the development of antioxidant and anticancer products.

9.2.4 Phaeophyceae Brown algae, in particular the orders Dictyotales and Fucales, are rich in secondary metabolites. Brown algae are recommended for treating cancer in Chinese and Ayurvedic medicinal texts (Hoppe et al., 1979; Yubin and Guangmei, 1998). Various seaweed extracts (e.g. Laminaria japonica, Porphyra tenera, Gelidium amansii and Euchema cottonii) dose-dependently inhibit growth of human gastric (AGS) and HT-29 colon cancer cells (Cho et al., 1997) and mammary tumours (Funahashi et al., 2001; Namvar et al., 2012). Brown seaweeds such as Laminaria are popularly used as food, and the incidence of breast cancer in Japan is about one sixth the rate of that reported for American women. Laminaria and Sargassum species are used in China as components of traditional herbal medicines for the treatment of cancer. The brown algae (Laminaria, Undaria or Ecklonia) have long been used by the Chinese and Japanese as sources of iodine (Yubin and Guangmei, 1998). Sulphated polysaccharides isolated from brown seaweeds Saccharina japonica (formerly named Laminaria) and Undaria pinnatifida have been tested successfully for their antitumour activity against human breast cancer T-47D and melanoma SK-MEL-28 cell lines (Olesya et al., 2012). Four phytochemicals, the xenicane diterpene 4-hydroxydictyolactone (i), and the diterpenes dictyol E (ii), 8,11-dihydroxypachydictyol A (iii) and indole-3carboxaldehyde (iv), isolated from Halimeda stuposa and a Dictyota sp., have

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320 Functional ingredients from algae for foods and nutraceuticals been tested for cytotoxic activities against human and mammalian cell lines SF-268, MCF-7, H460, HT-29 and CHO-K1. From these data, the first three compounds exhibit approximately similar activities against the three human tumour cell lines SF-268, MCF-7 and H460. However, the response of compounds i–iii against HT-29, a human colon tumour cell line, and CHO-K1, a Chinese hamster ovary non-tumour cell line, is between two- and four-fold less active as compared to those for the three cancer cell lines mentioned above. However, indole-3-carboxaldehyde is not active against any of the cell lines (Simon et al., 2012). The water extract of Sargassum oligocystum shows anticancer activity against human cancer cell line such as Daudi and K562. The result reveals that the cold water extract of S. oligocystum shows comparable activity to hot water extract. This reveals that bioactive compounds are heat sensitive (Zandi et al., 2010). Some other species of Sargassum: S. confusum, S. fusiforme, S. kjellmanianum and S. lomentaria exhibit antitumour activity along with immunostimulatory properties in tumour-bearing mice as well as apoptosis and cytotoxicity on selective human cancer cells (Gamal-Eldeen et al., 2009; Noda et al., 1990; Ogawa et al., 2004; Qy and Gy, 2004). Fucoidans from S. japonica and U. pinnatifida distinctly inhibit proliferation and colony formation in both breast cancer and melanoma cell lines in a dose-dependent manner. This proves that the use of sulphated polysaccharides from brown seaweeds S. japonica and U. pinnatifida are potential ingredients for cancer treatment (Olesya et al., 2011). Hexane extract of Padina minor inhibits the growth of cancer cell 1140 through topoisomerase I inhibition. The ethyl acetate extract also shows inhibition of strain 1353 which is sensitive to topoisomerase II inhibitors. The activity for the extracts is considered to be selective or specific as well as differential since the extracts do not show activity against other cell lines (Olesya et al., 2012). An extract from the brown seaweed Sargassum thunbergii and fucoidan fractions isolated from Fucus vesiculosus are shown to have antitumour activity (Zhuang et al., 1995) by inhibiting tumour metastasis in the rat mammary adenocarcinoma cell (13762 MAT) (Coombe et al., 1987). The low molecular weight fucoidan isolated from Ascophyllum nodosum inhibits the invasion of human breast cancer cells by blocking the accession of these cells in the extracellular matrix and it also inhibits the invasion of colon adenocarcinoma cells (Haroun-Bouhedja et al., 2002). The sulphated fucan, ascophyllan, isolated from the brown alga Ascophyllum has been tested for cytotoxicity against various cell lines (MDCK, Vero, PtK1, CHO, HeLa and XC). However, the polysaccharide shows cytotoxic effects only on Vero and XC cells, while other cell lines are relatively resistant to the polysaccharide (Jiang et al., 2010). The protective effect of edible seaweeds has been demonstrated against mammary, intestinal and skin carcinogenesis based on epidemiological data supported by rodent model studies (Yuan and Walsh, 2006). Fucoidans isolated from various species of brown algae show effective antitumour activities

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Anticancer agents derived from marine algae 321 both in vitro and in vivo. Some of the notable natural products discovered in the brown seaweeds are the fucoidans, glucans, some other secondary metabolites and their derivatives. These compounds are promising for anticancer activity. Meroterpenes are very common among the brown algae, especially in the order of Fucales. A series of 16 triprenyl and tetraprenylchromanes and sargachromanols A-P isolated from Sargassum siliquatrum and S. thunbergii shows the best antioxidant activity (Seo et al., 2006). Sesquiterpene quinines possess antitumour (Barrero et al., 1999) and immunomodulating (Bourguet Kondracki et al., 1991) activities. Aromatic oil such as stypoquinoic acid, derived from Stipodium zonales, is an inhibitor of tyrosine kinase and other derivatives including demathoxyatomaric acid are cytotoxic towards lung and colon cancers (Dorta et al., 2002, 2003). Bis-prenylated quinine from Perithalia capillaries under the order of Laminariales displays a strong antiproliferation of tumour cells. Prenylquinone and prenylated hydroquinones are common in Dictyotales and Fucales (Sansom et al., 2007). Many scientists have reported antioxidant and anticancer activities of sulphated polysaccharides isolated from marine algae (Rupérez et al., 2002) especially from F. vesiculosus, Laminaria japonica and Ecklonia kurome (Hu et al., 2001). Furthermore, porphyran, a sulphated polysaccharide isolated from Porphyra (Rhodophyta) has been reported to delay aging process in mice by enhancing the amount of antioxidative enzymes, thereby reducing the risk of lipid peroxidation (Zhang et al., 2003). The compound condriamide-A from Chondria sp., exhibits cytotoxicity towards human nasopharyngeal and colorectal cancer cells (Palermo et al., 1992). Phloroglucinol and its polymers, namely eckol (a trimer), phlorofucofuroeckol A (a pentamer), dieckol and 8,8’-bieckol (hexamers) isolated from the brown alga Eisenia bicyclis are shown to have anticancer activity (Nakamura et al., 1996; Shibata et al., 2002; Sithranga Boopathy and Kathiresan, 2010). The extract of the brown alga Taonamaria atomaria exhibits anticancer activity due to the compound, stypoldione which is an in vitro inhibitor of microtubule polymerization and it prolongs survival of mice injected with tumour cells due to low toxicity (Mayer and Lehmann, 2000). When native fucoidans are hydrolyzed in boiling water with hydrochloric acid for 5 min, it significantly increases anticancer activity. However, fucoidans hydrolyzed in a microwave oven display only little improvement in anticancer activity. This suggests that anticancer activity of fucoidans can be significantly enhanced by lowering their molecular weight only when they are depolymerized under mild conditions (Yang et al., 2008). Anticancer activity of fucoidans is found to be closely related to their sulphate content and molecular weight. The over-sulphated fucoidans effectively suppress the angiogenesis of Sarcoma 180 cells implanted in mice and exhibit more potent anticancer activity than native fucoidans (Koyanagi et al., 2003). The antiproliferative activity of over-sulphated fucoidan isolated from commercially cultured Cladosiphon okamuranus has been successfully tested

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322 Functional ingredients from algae for foods and nutraceuticals against U937 cells (Teruya et al., 2007.) It induces apoptosis via caspase-3 and -7 activation-dependent pathways. In addition, fucoidans extracted from C. okamuranus also induce apoptosis to human T-cell leukaemia virus type 1-infected T-cell lines and primary adult T-cell leukaemia cells. Antitumour activity of fucoidans from U. pinnatifida in PC-3, HeLa, A549 and HepG2 cancer cells behaves in a pattern similar to that of commercial fucoidans (Synytsya et al., 2010). According to another recent study, fucose rich sulphated polysaccharide from Ecklonia cava has antiproliferative effects on murine colon carcinoma (CT-26), human leukaemic monocyte lymphoma (U-937), human promyelocytic leukaemia (HL-60), and mouse melanoma (B-16) cell lines (Athukorala et al., 2009). Fucoidan inhibits proliferation and induces apoptosis in human lymphoma HS-Sultan cell lines. The fucoidaninduced apoptosis is accompanied by the activation of caspase-3 (Aisa et al., 2004). Another in vitro study has demonstrated the inhibitory effects of fucoidans on activation of epidermal growth factor receptor and cell transformation in JB6 C141 cells (Lee et al., 2008). Their results provide the first evidence that fucoidans from Laminaria guryanovae exert a potent inhibitory effect on EGF-induced phosphorylation of epidermal growth factor receptor (EGFR). In another recent study, antitumour and antimetastatic activities of fucoidans, isolated from the brown seaweed Fucus evanescens have been successfully tested against C57Bl/6 transplanted mice with Lewis lung adenocarcinoma (Alekseyenko et al., 2007; Wijesinghe and Jeon, 2012).

9.2.5 Rhodophyceae Secondary metabolites and their halogenated derivatives are abundant in red algae. A sesquiterpene elatol isolated from red alga Laurencia microcladia shows antitumour activity. Elatol exhibits a cytotoxic effect by inducing cell cycle arrest in the G1 and the sub-G1 phases, leading cells to apoptosis. Western blot analysis demonstrates that elatol reduces the expression of cyclin-D1, cyclin-E, cyclin-dependent kinase (cdk)2 and cdk4. A decrease in bcl-xl and an increase in bak, caspase-9 and p53 expression are also observed. In the in-vivo experiment, treatment with elatol is able to significantly reduce tumour growth in C57Bl6 mice (Campos et al., 2012). The ethanolic extract of calcareous red alga Corallina pilulifera has shown antiproliferative activity on human cervical adenocarcinoma cell line (HeLa). Another red seaweed, Acanthospora spicifera, exhibits tumouricidal activity against Ehrlich’s ascites carcinoma cells. This is evident from the increase in the mean survival time and decrease in tumour volume and viable cell counts (Vasanthi et al., 2004).It also controls the esophageal adenocarcinoma (EAC) in implanted mice (Lavakumar et al., 2012). The methanol, chloroform and ethanol extracts of Enteromorpha lingulata and Gracilaria edulis have been examined for antiproliferative activity on HCT15 cell line. The ethanolic extract of E. lingulata shows maximal inhibition of the cell line.

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Anticancer agents derived from marine algae 323 Porphyra tenera, a red alga, has been reported for its high anticarcinogenic effect. Extracts of this algal species can reduce intestinal tumour incidence in rats (Yamamoto et al., 1986). Also, carotene, lutein and chlorophyll-related compounds, isolated from algal species have been reported to exhibit strong antimutagenic activity in vitro and in vivo (Okai et al., 1996a). λ-Carrageenans isolated from Chondrus ocellatus have immunostimulant property and the carrageenans also enhance the antitumour activity of fluorovacil (5-FU) in mice transplanted with SIO and H-22 tumour (Yamada et al., 1997; Zhou et al., 2004, 2005, and 2006). Halomon extracted from Porteria hornemannii has strong cytotoxic action against several cancer cell lines (brain, kidney and colon) (Fuller et al., 1994; Sotokawa et al., 2000). A monoterpene isolated from P. hornemannii along with halomon acts as DNA methyl tranferase inhibitors (Andrianasola et al., 2006). Gracilarioside and gracilamides A and B, isolated from the red alga Gracillaria asiatica, show strong cytotoxicity for the A375–52 human melanoma cell line (Sun et al., 2006). Colpol is a phenolic derivative isolated from Colpomenia sinuosa and it exhibits cytotoxicity. A non-brominated derivative ‘preparguerene’ isolated from Laurencia filiformis displays cytotoxicity on several cell lines: B16, HeLa and P388 (Suzuki et al., 1989; Takeda et al., 1990). Teurilene, a tricyclic squelenoid from Laurencia obtusa shows strong cytotoxicity (Suzuki et al., 1985). The ethanolic extract of Gracilaria edulis shows effective anticancer activity against Ehrlic ascetic carcinoma (EAC) cells implanted in Wistar albino rats. The extract successfully improves the lifespan of the animals and prevents EAC (Sundaram et al., 2012). The water crude extract of red alga Gracilaria corticata has significant anticancer activity antitumour activity on Jurkat and molt-4 human lymphoblastic leukaemic cell lines (Zandi et al., 2010).

9.3

Mechanisms of anticancer activity

Several anticancer pathways are involved in order to execute the tumour cell death. However the exact mechanisms of the actions of marine algal samples vary with the nature of secondary metabolites present. Some of the major pathways are antioxidation and immune stimulation, ultimately leading to induction of programmed cell death (apoptosis), as depicted in Fig. 9.2.

9.3.1 Antioxidants Several mechanisms have been proposed for prevention of cancer both in vitro and in vivo. Radical scavenging is the major mechanism for preventing macromolecular damage by free radicals in the cells. It has been suggested that tumours are in a ‘pro-oxidant’ state generating more free radicals, which is usually accompanied by lack of DNA repair mechanisms and progression of cancer incidence. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as hydroxyl radical (•OH), hydrogen peroxide

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324 Functional ingredients from algae for foods and nutraceuticals Growth factors

Algal secondary metabolites

2 PTEN

1 PI(3)K

Endogenous free radical

Antioxidant

Exogenous free radical

AKT MDM2 DNA damage P53

BID

Nucleus P53

MDM2

Granzyme B

P53 tBID

P53 Gene expression

Mitochondria Bax

Bak Noxa

P53 degradation CTL (or) NK cell

Cyto C Apof1 Cancer

Apoptosome

Caspase-9 Caspase 3,6,7

3 Apoptosis

Algal primary metabolites

Fig. 9.2 Schematic representation of three principal routes of tumorigenesis and its control by primary and secondary metabolites of marine algae. Note: 1. Growth factors (Bcl2 family members) activate binding to RKT (receptor tyrosine kinase) and cause autophosphorylation of tyrosine residues on the intracellular domain of the receptor. Phosphoinositol 3-kinase (PI3K) is recruited to the phosphotyrosine residues and is therefore targeted to the inner cell membrane. Binding of PI3K to the phosphorylated RKT leads to conformational change in the catalytic domain of PI3K; negative regulation of p53 by Akt is induced in response to survival signals from MDM2. The activation of this pathway leads to the inhibition and destruction of p53. Under stress conditions, this pathway is blocked through the cleavage and degradation of Akt and the inhibition of PI3K through phosphatase and tensin homologue (PTEN). In this mechanism anticancer action is executed through the marine algae-derived secondary metabolites such as phenolics which scavenge free radicals of both endogenous and exogenous origin, thereby blocking the whole process of tumourogenesis mediated through p53 degradation. 2. Free radicals of both endogenous and exogenous origin cause DNA damage resulting in activation of p53 inside the cell nucleus. The p53 induces the protein subunits such as Bax and NOXA Bak present in the cell mitochondria resulting in excretion of cytochrome-C from mitochondria to cytosol. The cytochrome-C complexes with apof-1 and caspase-9 to form an apoptosome ultimately leading to apoptosis. In this mechanism anticancer action is executed through the marine algae-derived secondary metabolites such as phenolics which scavenge free radicals, thereby preventing DNA damage. 3. Algal primary metabolite such as polysaccharides stimulates cytotoxic T lympocytes (CTC) (or) natural killer cells (NKCs) outside the cell. These factors will induce accumulation of granzyme B and BID in cytosol which in turn stimulates tBID in mitochondria. This results in cytochrome-C excretion and apoptosome formation, ultimately leading to apoptosis.

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Anticancer agents derived from marine algae 325 (H2O2), superoxide (O2•-), nitric oxide (NO•), peroxynitrite (ONOO-) and others, are major sources of oxidative stress in cells, damaging proteins, lipids and DNA (Orrenius et al., 2007). Oxidative macro molecular damage has been implicated as a major cause of cancer (Hajiliadis, 1997; Huang, 2003). Free radical species can increase proliferation, cell cycle arrest, or induce senescence, apoptosis or necrosis. Two types of antioxidants which scavenge free radicals play a role in cancer, such as exogenous antioxidants incorporated mostly by dietary intake, and also those endogenous antioxidants which contribute to control normal cellular redox status. ROS/RNS can participate at multiple levels of carcinogenesis, either by direct effects on DNA or by modulating signalling pathways leading to an increase in cell proliferation. However, the direct role of ROS/RNS in carcinogenesis is mostly related to initiation and promotion, whereas the rest of the tumour stages can be indirectly related to free radicals through the chronic inflammation-related deregulation of immunological factors such as cytokines released by macrophages (Karin, 2006). Antioxidants inhibit the growth of cancer cells through diverse mechanisms. The major mechanism is activation of apoptosis by antioxidants and inhibition of tumour progression. Many of the natural antioxidants may trigger the apoptosis by expression of p53 mediated proteins such as BID, BAX, and PUMA and prevent the expressions of the following survival proteins (Bcl-2, Bcl-XL, IAP) in the cancer cells. Antioxidants are important inhibitors of lipid peroxidation, a defence mechanism of living cells against oxidative damage. They delay or prevent the oxidation of cellular oxidizable substrates. Antioxidants exert their effects by scavenging ROS, activating a battery of detoxifying proteins, or preventing the generation of ROS (Jun et al., 2001). Therefore, there is a need for isolation and characterization of natural antioxidant having less or no side effects, for use in foods or medicinal materials to replace synthetic antioxidants. Marine algae have received special attention as a source of food and medicine such as antioxidative and anticarcinogenic properties (Matsukawa et al., 1997; Athukorala et al., 2003; Lim et al., 2002).

9.3.2 Induction of programmed cell death (apoptosis) In 1842, Carl Vogt described the concept of natural cell death for the first time. The word ‘apoptosis’ is of Greek origin. Apoptosis was originally defined in 1972 in the development of cancer and other diseases (Ker et al., 1972). It is a programmed cell death that occurs in unfavourable situations. This essential process can be initiated by either extrinsic or intrinsic stimuli, and is of fundamental importance in the maintenance of tissue homeostasis of multicellular organisms. However, various factors including signal molecules, receptors, enzymes and gene-regulating proteins determine the induction and execution of apoptosis. Among them, the protein p53 and caspase-cascade signalling

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326 Functional ingredients from algae for foods and nutraceuticals system are prime factors for executing apoptosis, which is regulated by various molecules such as the inhibitor of apoptosis protein (IAP), Bcl-2 family of proteins and calpain (Launay et al., 2005). Caspases, the interleukin-1βconverting enzyme family of proteases, are highly homologous to cell death gene of CED-3 derived from the nematode Caenorhabditis elegans. Fourteen caspases have been identified so far; of them, seven are responsible for apoptosis and the remaining ones are inflammatory mediators. Apoptosis has three stages, namely activation, execution and cell deletion. These stages are interlinked by the action of cysteine-dependent aspartate-specific enzymes, proteases or caspases (Fan et al., 2005). Once activated, caspases cleave other key proteins, cytoskeletal elements, cell adhesion molecules and conclude with endonuclease cleavage of nuclear material and cell disposal (Woo et al., 2004). The p53 tumour suppressor protein induces cell growth arrest and triggers the apoptosis. The prevention of cancer is profoundly dependent on p53 for controlling the proliferation of cells with damaged DNA or with a potential for neoplastic transformation. The p53 is activated by external and internal stress signals that promote its nuclear accumulation in an active form. However, the p53 activities are suppressed by gene mutations in 50% of human cancers, and in the remaining cancer cases the p53 activities are inhibited by elevated levels of p53 inhibitors, such as MdM2 or the E6 protein of HPV, or silencing of key p53 co-activators, such as ARF (Vogelstein et al., 2000; Vogt Sionov et al., 2001). Under normal conditions, the rate of p53 protein expression in the cell is maintained at very low levels, and is strictly controlled by its important negative regulator MDM2 (also known as HDM2 in humans) (Vousden and Lu, 2002). MDM2 and p53 regulate each other through an autoregulatory feedback loop. The MDM2 activity is also modulated by its structural homologue partner protein called MDMX (Brown et al., 2009). The MDM2-MDMX complex is a common to target proteosome-mediated degradation of p53. MDM2 also inactivates p53 by repressing its transcriptional activity (Brown et al., 2009; Vousden and Lane, 2007; Wiman, 2010). Like MDM2, MDMX also binds directly to p53 and inhibits its transcriptional activity; however, it does not induce p53 degradation (Bottger et al., 1999; Shangary and Wang, 2008). ARF tumour suppressor plays a crucial role in protecting and stabilizing p53 from MDM2-induced degradation (Brown et al., 2009). The status of p53 is drastically altered when the cells are exposed to stress, including DNA damage, untimely expression of oncogenes, hypoxia and nucleotide depletion (Giaccia and Kastan, 1998). Many phytochemicals from algae cause apoptosis. The two most common edible cyanobacteria include Spirulina and Aphanizomenon flos-aquae (AFA) (Hart et al., 2007); both contain phycocyanin, a molecule that is capable of showing apoptosis in the chronic myeloid leukaemia cell line, K562 (Subhashini et al., 2004), and other types of cancer (Basha et al., 2008; Li et al., 2010). Enzymatic extraction of alga, E. cava together with its crude polysaccharides and crude polyphenolics, displays tremendous antiproliferative activity against

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Anticancer agents derived from marine algae 327 cancer cell line. The suppressive effect of extracts on CT-26 cell proliferation is related to apoptotic body formation as a result of DNA damage and protein damage. While DNA damage initiates death signalling, protein damage distorts the cell redox homeostasis, which facilitates apoptosis execution.

9.3.3 Immune stimulation Immune defence mechanisms do kill any abnormal cells including cancer. The apoptosis is executed immunostimulation through two major pathways such as NK cell and Fas receptor mediated pathways. The NK cell pathways, on contact with target cells, cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells exocytose the granules that contain perforin and granzymes into target cells. Granzyme B cleaves BID to generate a tBID fragment, which binds to mitochondria and leads to the release of cytochrome-C into the cytosol (Hersey and Zhang, 2001). Subsequently, an apoptosome is formed to execute the apoptosis. In another pathway, the Fas receptor molecule plays an important role in the immune system, allowing the removal of autoantibodies and the elimination of virally infected and tumourigenic cells. When activated by Fas ligand (FasL), the receptor (Fas) trimerizes, resulting in the cleavage of a caspase that binds to its intracellular domain via death domain proteins. The activated caspase then initiates the cascade of proteolytic cleavage (Fig. 9.2). In 1979, Russian scientists carried out pioneering research on the immune-stimulating effects on rabbits of lipopolysaccharides from Spirulina (Besednova et al., 1979). The algal sulphated polysaccharides were reported to influence innate immunity to reduce the pro-inflammatory state or other detrimental conditions such as allergic reactions arising during the innate immune response. In addition, there is evidence that algal polysaccharides can regulate the innate immune response directly by binding to pattern recognition receptors (PRRs) such as the mannose receptor and toll-like receptors on phagocytic cells including macrophages (Chen et al., 2008). The direct stimulatory effects of algal polysaccharides on immune cells results in production of nitric oxide through induction of inducible nitric oxide synthase (iNOS) and a pro-inflammatory cytokine/chemokine profile (Leiro et al., 2007). Depending on the situation, the interaction of sulphated polysaccharides with other effectors may result in reduced inflammation. For example, fucoidan from F. vesiculosus induces iNOS in RAW264.7 macrophage cells leading to enhanced production of nitric oxide (Nakamura et al., 2006; Yang et al., 2006). Yet, in the presence of lipopolysaccharide (LPS), the fucoidan impairs LPS-induced expression of iNOS and nitric oxide production (Yang et al., 2006). Similarly, fucoidan suppresses interferon gamma-induced iNOS expression in macrophage and glial cells (Do et al., 2010). Algal polysaccharides increase macrophage function, antibody production and infection-fighting T-cells. Spirulina has been taken as a nutritional

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328 Functional ingredients from algae for foods and nutraceuticals supplement for many years and has shown no undesirable side effects (Gershwin and Belay, 2008); it is also the source of immunomodulator. Orally administered Spirulina extract has been shown to enhance tumouricidal Natural Killer cell activation through the MyD88 pathway, and Spirulina exerts a synergistic antitumour activity with the BCG-cell wall skeleton when used as immunotherapy for melanoma (Akao et al., 2009). The biological activities of some microalgal species are known to be associated with polysaccharides. Polysaccharide complexes from Chlorella pyrenoidosa contain glucose and any combination of galactose, rhamnose, mannose, arabinose, N-acetylglucosamide and N-acetylgalactosamine. These complexes have immunostimulating properties and can inhibit the proliferation of pathogenic microbes such as Listeria monocytogenes and Candida albicans (Spolaore et al., 2006). The most important substance in Chlorella is β-1,3-glucan, which is an active immunostimulator, a free radical scavenger and a reducer of blood lipids. Enteromorpha compressa, an edible green alga, produces an array of bioactive compounds which are proved to be useful in the treatment of cancer and inflammation (Higashi-Okai et al., 2000; Okai and Higashi-Okai, 1997). Low molecular weight λ-carrageenans isolated from Chondrus ocellatus have potent immunostimulant properties and they also enhance the anti-tumour activity of fluorouracil in mice transplanted with S10 H-22 tumours (Yamada et al., 1997; Zhou et al., 2004, 2005, 2006). Malyngamides isolated from Lyngbya majuscula have potent cytotoxicity and immunosuppressant properties (Burja et al., 2001).

9.4

Conclusions

Although marine compounds are under-represented in current pharmacopoeia, the marine environment will become an invaluable source of novel compounds in the future, as it represents 95% of the biosphere (Jimeno, et al., 2004). However, development of marine algal compounds as therapeutic agents is still in its embryonic stage due to the lack of an analogous ethno-medical history as compared to that for terrestrial habitats. Over the last few decades, significant efforts have been made by both pharmaceutical companies and academic institutions, to isolate and identify novel marinederived compounds from faunal species, in particular invertebrates (Sithranga Boopathy and Kathiresan, 2010). However, marine algae have been relatively little explored for anticancer compounds, and this deserves special attention. Marine algae have been used as food and in traditional medicine because of their health benefits (Athukorala et al., 2003; Cahyana et al., 1992; Fujimoto and Kaneda 1984; Rupérez et al., 2002; Yan et al., 1998). Marine algae produce a variety of bioactive compounds, some of which possess potential medicinal values (Konig et al., 1994; Moore, 1978). Among the five divisions of microalgae, studies of biomedical products have been concentrated on only two divisions, that is, Cyanophyta (blue-green algae) and Pyrrophyta

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Anticancer agents derived from marine algae 329 (dinoflagellates). Marine algae are promising largely for pharmacological research towards the development of anticancer therapy.

9.5

Acknowledgements

The authors are grateful to the authorities of Annamalai University for providing facilities and to the University Grants Commission (UGC) for offering a post-doctoral fellowship (N.S.B).

9.6

References

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