Keywords

1.1 Introduction

Cancer is a dreadful human disease, increasing with changing life style, nutrition, and global warming. A report released by the World Health Organization (WHO) showed that an estimated 12.7 million people were diagnosed with cancer globally and about 7.6 million people died of it in 2008. As estimated in this report, more than 21 million new cancer cases and 13 million deaths are expected by 2030. Although cancer accounts for around 13 % of all deaths in the world, more than 30 % of cancer deaths can be prevented by modifying or avoiding key risk factors [1]. However, almost all of the chemotherapy drugs currently in the market cause serious side effects. Natural products and their derivatives represent more than 50 % of all the drugs in clinical use of the world. Higher plants contribute not less than 25 % of the total. Almost 60 % of drugs approved for cancer treatment are of natural origin. Although marine compounds are underrepresented in current pharmacopoeia, it is anticipated that the marine environment will become an invaluable source of novel compounds in the future [2].

Marine nutraceuticals can be derived from a vast array of sources, including marine plants, microorganisms, and sponges. Marine nutraceutical products currently promoted to various countries include fish oil, chitin, chitosan , marine enzymes and chondroitin from shark cartilage, sea cucumbers and mussels. Polysaccharides derived from alga, including alginate, carrageenan and agar are widely used as thickeners and stabilizers in a variety of food ingredients. In addition, Omega PUFA (Polyunsaturated fatty acid) is an important ingredient to the nutraceutical industry [3]. It has been proven that Omega-PUFA, especially eicosapentaenoic acid (EPA) and docosahexenoic acid (DHA) play a significant role in number of aspects of human health [4].

More than 70 % of our planet’s surface is covered by oceans. An exciting “marine pipeline” of new anticancer clinical and preclinical agents has emerged from intense efforts over the past decade to more effectively explore the rich chemical diversity offered by marine life. The chemical adaptations generally take the form of so-called “secondary metabolites,” and involve such well known chemical classes as terpenoids , alkaloids, polyketides, peptides, shikimic acid derivatives, sugars, steroids, and a multitude of mixed biogenesis metabolites. In addition, and unique to the marine environment, is the relatively common utilization of covalently bound halogen atoms in secondary metabolites, mainly chlorine and bromine, presumably due to their ready availability in seawater [5, 6]. Marine compounds that act as hallmarks of cancer presented namely self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis , limitless replication, sustained angiogenesis and tissue invasion and metastasis [7–11].

1.2 Sponges

Marine sponges for the past decades have been considered as a very fertile field for the discovery of bioactive natural chemical substances with respect to the diversity of their primary and secondary chemical components and metabolites. Marine sponges (Porifera) are the oldest metazoan group, having an outstanding importance as a living fossil [12]. There are approximately 8000 described species of sponges and perhaps twice as many un-described species [13, 14]. Sponges inhabit every type of marine environment, from polar seas to temperate and tropical waters and also thrive and prosper at all depths. They show an amazing variety of shapes, sizes and colours. Giant barrel sponges can reach up to 70 in. in height, while another tiny encrusting sponge may only be half of an inch long. Sponges are sessile organisms. However, due to their cellular plasticity, many sponges reorganize their bodies continuously and move during this process very slowly [14]. Marine sponges through evolutionary and ecological long term changes often contain diverse microbial communities (bacteria, archaea, microalgae, fungi) which comprise as much as 40 % of the sponge volume and can contribute significantly to host metabolism (e.g., via photosynthesis or nitrogen fixation). The ecological and evolutionary importance of sponge-microbe associations can be mirrored by their enormous biotechnological potential producing a great range of bioactive metabolites [15, 16]. Scientist has discovered more than 5000 species and also there are more than 8000 marine sponges on Earth.

Marine sponges have been ranked at the top with respect to the discovery of bioactive compounds with potential pharmaceutical applications. The diversity in chemical structures of sponge-derived metabolites is related to an equally diverse pattern of activities. The chemical diversity of sponge natural products is remarkable, including unusual nucleosides, bioactive terpenes, sterols, cyclic peptides , alkaloids, fatty acids, peroxides, and amino acid derivatives (which are frequently halogenated) [17]. In the field of natural products chemistry and research suggest that sponges have the potential to provide future drugs against some important diseases, such as viral diseases, malaria, inflammations, immunosuppressive diseases and various malignant neoplasms [5, 18–20]. In the last few years there are several other candidates from marine natural compounds in the pipeline for evaluation in Phase I–III clinical trials for the treatment of various cancers [21, 22]. From the previous studies, marine natural compounds from sponge species were undergoing preclinical and clinical trials (I, II, III) for anticancer activity. Among the compounds were discodermolide, hemiasterlins A & B, modified halichondrin B, KRN-70000, Alipkinidine (alkaloid), fascaphysins (alkaloid), isohomohalichondrin B, Halichondrin B, Laulimalide/Fijianolide, 5-methoxyamphimedine (alkaloid) and Variolin (alkaloid) [16]. In recent years, new marine-derived antiangiogenic agents have been widely investigated. At least 43 marine-derived natural products and their derivatives have been reported to display antiangiogenic activities, mediated by distinct or unknown molecular mechanisms [16, 23].

The first successful sponge-derived pharmaceutical drugs were the nucleosides spongothymidine and spongouridine which were isolated from Tectitethya crypta [24]. A derivative of these nucleosides, Ara-C (also known as 1-beta-d-Arabinofuranosylcytosine or cytarabine) is documented as the first marine derived anticancer agent that is recently used for the treatment of leukemia [25, 26]. An overview (2011) retrieved scientific papers identifying 39 compounds from marine sponges with apoptosis-inducing anticancer properties [27]. Renieramycins are members of the tetrahydroiso-quinoline family that were isolated from marine sponges belonging to genera Reniera induces apoptosis through p53-dependent pathway and may inhibit progression and metastasis of lung cancer cells [28]. Monanchocidin is a novel polycyclic guanidine alkaloid isolated from the marine sponge Monanchora pulchra that promote cell death in human monocytic leukemia (THP-1), human cervical cancer (HeLa) and mouse epidermal (JB6 Cl41) cells [29]. Smenospongine, a sesquiterpene aminoquinone, from the sponge Smenospongia sp. have antiproliferetive and antiangiogenic activities [30]. The macrocyclic lactone polyether spongistatin 1 was isolated from the marine sponge Spongia sp. [31], inhibit mitosis, microtubule assembly and inducing cytotoxic cell death in numerous cancer cell lines [32]. Recently, scientists purified a lectin from the marine sponge Cinachyrellaapion (CaL) have hemolytic, cytotoxic and antiproliferative properties and cell death in tumor cells [33]. Heteronemin, a marine sesterterpene isolated from the sponge Hyrtios sp., inhibits chronic myelogenous leukemia cells by regulating cell cycle, apoptosis , mitogen-activated protein kinases (MAPKs) pathway and the nuclear factor kappaB (NF-kappaB) signaling cascade [34]. Still there are number of anticancer compounds is isolated and screened form marine sponges .

1.3 Algae

Algae are relatively undifferentiated organisms which, unlike plants, have no true roots, leaves, flowers or seeds. They are found in marine, freshwater and terrestrial habitats. Their size varies from tiny microscopic unicellular forms of 3–10 µm (microns) to large macroscopic multicellular forms up to 70 m long and growing at up to 50 cm per day. Most of the algae are photosynthetic organisms that have chlorophyll. Marine macroalgae are important ecologically and commercially to many regions of the world, especially in Asian countries such as China, Japan and Korea [35]. Phytoplankton, seaweeds and symbiotic dinoflagellates (unicellular, biflagellate organisms) in corals and sea anemones are marine algae. Seaweeds are classified as green algae (Chlorophyta), brown algae (Phaeophyta), red algae (Rhodophyta) and some filamentous blue-green algae (Cyanobacteria). Most of the seaweeds are red (6000 species) and the rest known are brown (2000 species) or green (1200 species). Seaweeds are used in many maritime countries as a source of food, for industrial applications and as a fertilizer. Industrial utilization is at present largely confined to extraction for phycocolloids, industrial gums classified as agars, carrageenans and alginates. Carrageenans, extracted from red seaweeds such as Chondrus, Gymnogongrus, and Eucheuma among others, are used to provide particular gel qualities. Alginates are derivatives of alginic acid extracted from large brown algae such as Laminaria. They are used in printers’ inks, paints, cosmetics, insecticides, and pharmaceutical preparations .

Seaweeds have been one of the richest and most promising sources of bioactive primary and secondary metabolites [36]. The algae synthesize a variety of compounds such as carotenoids, terpenoids , xanthophylls, chlorophyll, vitamins, saturated and polyunsaturated fatty acids, amino acids, acetogenins, antioxidants such as polyphenols, alkaloids, halogenated compounds and polysaccharides such as agar, carrageenan, proteoglycans, alginate, laminaran, rhamnan sulfate, galactosyl glycerol and fucoidan [36, 37]. These compounds probably have diverse simultaneous functions for the seaweeds and can act as various functions including anticancer effects. The seaweeds are the rich source of carotenoids, the most notable being β-carotene, α-carotene, fucoxanthin, astaxanthin, canthaxanthin, zeaxanthin and lutein has been reported as effective antioxidants. Seaweed carotenoids are powerful antioxidants associated with the prevention of cardiovascular, neurodegenerative diseases and also cancer. The carotenoids have been extensively studied and the consumption of the dietary carotenoids has been correlated with cancer prevention [38, 39]. Also, amelioration effect of green sea algae derived compound dimethylsulfonioacetate (DMSP) has shown that on stress and aging closely related to cancer, solid and free cell cancer, and neural degeneration caused by brain cancer with model animals .

1.4 Microbes

Microbes, like this single-celled marine phytoplankton, make up a staggering 90 %of the ocean’s total biomass. Marine microbes are tiny organisms that live in marine environments and can only be seen under a microscope. They include cellular life forms such as bacteria, fungi and plankton along with the viruses that freeload on the cellular life forms. There are more than a billion micro-organisms living in each litre of seawater, and it is now known that microbes dominate the abundance, diversity and metabolic activity of the ocean. Marine microbes are having huge biochemical diversity and rich source of novel drugs. Marine microbial compounds are an important source for drug development [40]. Marine bacteria are one of the important sources for many bioactive compounds , antibiotics and pharmaceuticals. They are usually found in the marine sediments and also found to be associated with the marine organisms [41]. Despite a limited number of marine microbial antitumor agents currently on the market or in clinical trials, there are strong evidences that some promising marine natural compounds in clinical trials as well as some approved marine-derived anticancer agents produced by invertebrates, in fact metabolic products of their associated microorganisms, or derived from a diet of prokaryotic microorganisms [42, 43].

Meroterpenoids are a class of secondary metabolites in which the terpenoid moieties are linked to molecules from different biosynthetic pathways. Meroterpenoids containing quinones are also widespread in marine microorganisms , with prenylated naphtoquinones and reduced hydroquinone analogues are reported from marine microorganisms especially fungi and actinomycetes [44]. Meroterpenoids especially those with anticancer activity, produced by all types of marine-derived microorganisms. Marine fungi are also reported as a potential source for bioactive compounds . Polyketide synthases are a class of enzymes that are involved in the biosynthesis of secondary metabolites. The microbe’s derived compounds are potential use for anticancer research.

Actinomycetes are one of the most efficient groups of secondary metabolite producers, they exhibit a wide range of biological activities and also anticancer effects. Several species have been isolated and screened from the soil in the past decades. Among its various genera, Streptomyces, Saccharopolyspora, Amycolatopsis, Micromonospora and Actinoplanes are the major producers of commercially important biomolecules [45]. Actinomycetes are virtually unlimited sources of new compounds with many therapeutic applications and hold a prominent position due to their diversity and proven ability to produce novel bioactive compounds [46]. In the search for bioactive compounds from actinomycetes collected from the deep-sea water in Toyama Bay, two new glycosylated polyketides were isolated from the culture extract of Micromonospora sp., the arisostatin A and arisostatin B, respectively [47, 48]. Arisostatins are the new members of tetrocarcin-type cytotoxic compounds. Arisostatin A showed a potent cytotoxic effect on human cancer cells and activates caspase 3, a key effector protease responsible for apoptosis induction [49].

Marine fungi have proven to be untapped resources for the rich and promising source of novel antibacterial, antiplasmodial, anti-inflammatory antiviral and anticancer agents. Most of the fungi grow in unique and extreme environments therefore they have the ability to generate unique and unusual secondary metabolites [50]. Toluquinol is derived from marine fungus interferes with one of the hallmarks of cancer described by Hanahan and Weinberg by impairing the unlimited replicative potential, characteristic of tumor cells. Toluquinol represses the proliferation of the promyelocytic leukemia HL60 cell line, fibrosarcoma HT1080 cell line and colon adenocarcinoma HT29 cell line. The IC50 values, which represent the concentrations of toluquinol yielding a 50 % of cell growth, were lower than 10 µM in the three cell lines and also inhibits angiogenesis of cancer [51]. Diketopiperazines (DKPs) of marine resources, especially those isolated from marine-derived fungi , have been paid increasing attention for their diversity in chemical structure and bioactivity. Halimide ((-)-phenylahistin) is a fungal prenylated DKP isolated from Aspergillus ustus NSC-F038 and arrested the cancer cell cycle of P388 in the G2/M phase [52].

1.5 Tunicates

Tunicates are also known as urochordates, belong to the subphylum Tunicata or Urochordata. Tunicates have been shown as a primitive model organism to study immunodefense since the innate immune system has been hypothesized as an important functional component that may partially explain the lack of metastatic tumors in invertebrates [53]. Marine-derived compounds have reached clinical trials as antitumor from tunicates such as didemnin B, Aplidine , and ecteinascidin 743. Didemnin B (DB), a cyclic depsipeptide from the compound tunicate Trididemnum solidum, was the first marine-derived compound to enter Phases I and II clinical trials. The Phase II studies, sponsored by the U. S. National Cancer Institute, indicated complete or partial remissions with non-Hodgkins lymphoma, but cardiotoxicity caused didemnin B to be dropped from further study. The closely related dehydrodidemnin B (DDB, Aplidine) was isolated in 1988 from a second colonial tunicate, Aplidium albicans, and spectroscopic studies assigned a structural formula in which a pyruvyl group in DDB replaced the lactyl group in DB and syntheses of DDB have been achieved. Aplidine is more active than DB and lacks DB’s cardiotoxicity. The second family of tunicate-derived antitumor agents are the ecteinascidins (ETs), from the mangrove tunicate Ecteinascidia turbinata. The antitumor extracts of E. turbinata were first described in 1969, but the small amount of ETs in E. turbinate prevented their isolation for over a decade. Phase II clinical trials with ET 743 are underway [54] .

1.6 Miscellaneous

In recent years, marine natural product bioprospecting has yielded a considerable number of drug candidates. Research into the ecology of marine natural products has shown that many of these compounds have anticancer function [43]. Apart from sponge, algae , tunicate, microbes other marine organisms include sea cucumber, sear hare, mollusks and Bryozoans derived marine natural products also has a anticancer function include microtubule-interfering agents, DNA-interactive agents, phosphatase inhibitors etc. Alkaloids pyridoacridines isolated from various marine sources have been reported to possess significant cytotoxicity against cultured cells, and the family as a whole seems to be of great interest as a source of new lead structures for the development of future generation of therapeutic agents [55]. Sea cucumbers are one of the marine animals which are important as human food source, and sea cucumber extracts have been used for over-the-counter dietary health supplements [56, 57]. Triterpene glycosides from sea cucumbers demonstrate that wide spectrum of biological effects, such as antifungal, antitumor , hemolytic, cytostatic, pro-apoptotic and immunomodulatory activities. Frondoside A and Cucumariosides showed cancer preventive effects on both in vitro and in vivo models [58–60]. The dolastatins were originally reported from the Indian Ocean sea hare, Dolabella auricularia. Subsequently, a number of dolastatins and related molecules were isolated from filamentous marine cyanobacteria , which are the natural diet of the sea hares [61]. The dolastatins is the most active molecule in inhibiting cancer cell growth [62].

Meroterpenes are a class of natural products that exhibit a remarkable chemical diversity. This rich chemistry is a consequence of their mixed biosynthesis , as they are composed of an aromatic moiety/carbohydrate residue and also a terpenoid portion that can range from one to nine isoprene units. Prenylated quinone/hydroquinone derivatives are amongst the most numerous and widespread in marine environment [63, 64]. Meroterpenes are not exclusive to marine organisms , being found also in many terrestrial species. This type of compounds has various biological functions including anticancer effects. In the marine environment, the main sources of meroterpenes are brown algae , microorganisms, soft corals and marine invertebrates , such as sponges or ascidians [64]. Number of bacteria and cyanobacteria associated with the marine sponges have been found to be the sources of antibiotics and other bioactive compounds and it has been reported that the wider biosynthetic capabilities of sponges are associated with their symbiotic microorganisms [65]. IB-96212, a 26-membered macrolide that contains a spiroketal lactone structure, is produced by the actinomycete, Micromonospora sp. L-25-ES25-008, isolated from a sponge, collected from the Indian Ocean near the coast of Mozambique [66] and showed cytotoxic activity against mouse leukemia P-388 and human lung nonsmall cell A-549, colon adenocarcinoma HT-29 and melanoma MEL-28 cell lines [67]. Cembrane-type diterpenoids are a large and structurally varied group of natural products isolated from both terrestrial and marine organisms [68]. In the marine environment, coelenterates of the orders Alcyonacea and Gorgonacea are recognized as the most prominent source of cembranoids, which usually exhibit cyclic ether, lactone, or furane moieties around the cembrane framework [69–71]. The diterpenoids of the cembrane family have been shown to biomedical perspective, cytotoxicity is the most remarkable property of this class of diterpenoids [72].

1.7 Research Scope

Marine environments play a vital role in exploring and studying various marine resources and isolation, characterization and applications of biological active compounds from marine field. The sea covers over 70 % of the earth’s surface and large proportion of the sea offers untapped sources of potential drugs with promising activities due to a large diversity of marine habitats and environmental conditions (nutrient availability, sunlight presence, and salinity levels). In the area of marine research, a recent census of marine life that involved the participation of 2700 scientists from over 80 nations assessed the diversity, distribution and abundance of marine life resulted in the discovery of over 6000 potentially novel species (Census of marine life. http://www.comlorg/about-census).

The anticancer research progress in throughout the world including Republic of Korea, Japan, India, China, Singapore, Malaysia, Australia and USA, as well as others countries also in importance as a research priority for finding new anticancer compounds from marine sources. However, advances in drug discovery are expected to encourage applications from the marine field. A major task of marine is to develop an efficient process for the discoveries of novel molecules from the marine environment. The huge level of marine biodiversity of marine organism makes them a prime target for the productions of enzymes and bioactive molecules for the treatment of various diseases including cancer . Biochemical studies of marine organisms are an important task for the discovery of new drug molecules and biological tools and management of biodiversity. These research efforts, it is clear that the marine environment represents an important source of unknown natural compounds whose medicinal potential must be evaluated. Almost 50 % of the antitumor agents approved in the last 50 years of the twentieth century were either compounds derived from natural sources or (semi-) synthetic analogs of these products. Natural compounds remain a high output source of promising chemotherapeutic or chemopreventive agents in current cancer research. In addition to PharmaMar, other pharmaceutical companies including Bedford, Enzon, Eisai Inc., Novartis, Aventis, Eli Lilly, Abbott In”azyme, Pfizer and Taiho Pharmaceuticals Co., have therapeutic compounds of marine origin under development.

1.8 Organization of Handbook

This handbook combines the knowledge about the compounds isolated from sponge, algae , microbes, tunicates etc and also methods, product development, industrial and biomedical applications. This handbook is divided into five parts. The first part of the book comprises the introduction, sponges, microbes, algae, tunicates and other miscellaneous compounds derived from other marine organisms . The second part deals with sponge derived drug discovery represent one of the most promising sources of leads in the research of new cancer drugs. These chapters provide an overview of the angiogenesis inhibitors isolated from marine sponges based on the available information regarding their primary targets or mechanism of action and antitumour effect of triterpenoids , cyclic peptides and cyclodepsipeptides also discussed. Moreover, marine sponge derived compound eribulin with respect to its clinical pharmacology, pharmacokinetics, pharmacodynamics, mechanism of action, metabolism, preclinical studies and clinical trials. The third part of the book introduces about the marine algae derived compounds on cancer targets. In this amelioration and anti tumor effect of a tertiary sulfonium compound, dimethylsulfoniopropionate , from green sea algae and the various biological functions including anticancer effects of the seaweed carotenoids such as fucoxanthin etc. and the possible mechanisms of action are described. Fucoidan , a sulfated polysaccharides isolated from brown algae , anticancer and antimetastatic action are described. The health benefits of marine algae have been intensively investigated for human. The seaweeds biological roles and potential benefits for female cancers to be discussed in this part.

The fourth part of the book provides the details about marine microbial derived compounds for cancer therapeutics. In this chapter provide evidence on the antitumor compounds isolated from marine microbes such as fungai, bacteria and actinobacteria. The fifth part of the book dealt with marine tunicate derived compounds for cancer therapeutics . Finally the sixth part of the book covers others marine organisms derived compounds for cancer to be discussed. In this part deals the structures and sources of the isolated marine pyridoacridine alkaloids , as well as the mechanisms underlying the cytotoxicity of certain naturally occurring marine pyridoacridines. Anticancer effects of triterpene glycosides, Frondoside A and Cucumarioside A2–2 isolated from sea cucumbers. Discovery and computer-aided drug design studies of the anticancer marine triterpene sipholanes as novel P-gp and Brk modulators. Molecular targets of anticancer agents from filamentous marine cyanobacteria . Cytotoxic terpene-purines and terpene-quinones from the sea cytotoxic triterpene glycosides from sea cucumbers. Meroterpenes from marine invertebrates chemistry and application in cancer. Marine sponge derived actinomycetes and their anticancer compounds . Advances of microtubule-targeting small molecular anticancer agents from marine origin. Targeting cellular proapoptotic agents from marine sources. Cytotoxic cembrane diterpenoids. Pederin , psymberin and the structurally related mycalamides biological activities, P-gp inhibitory activity from marine sponges, tunicates and algae.