Indian Journal of Geo-Marine Science Vol. 44(7), July 2015, pp. 961-970

REVIEW ARTICLE

Marine molluscs as a potential drug cabinet: an overview

Premalata Pati*, Biraja Kumar Sahu & R. C. Panigrahy Department of Marine Sciences, Berhampur University, Berhampur-760007, Odisha, India *[ Email: [email protected] ]

Received 21 April 2014; revised 6 June 2014

Marine molluscs have emerged as an important source containing numerous unique secondary metabolites which could be used for development of new drugs against many communicable and non-communicable deadly diseases. The current status of biologically active compounds extracted, identified and isolated from marine molluscs and tested for their anti-cancer, anti-inflammatory and anti-microbial activities together with important compounds isolated from them such as Dolastatin 10 & 15, Kahalalide F, Keenamide A, Spisulosine-ES-285 etc. which possess anti-cancer and Ziconotide having anti-inflammatory properties are discussed in this paper. [Keywords: Marine molluscs, bioactive compounds, drugs]

Introduction spread of many incurable and fatal diseases like As many as 34 phyla, of the total 36 known influenza, diabetes, coronary disorder, AIDS and phyla were reported from marine cancer globally. Again, many disease causing biosphere against 17 phyla from land1-4. The plant pathogens became drug resistant giving rise to components in sea contain all classes of algae (as their mutant forms. Coupled with such threat phytoplankton and seaweeds), angiosperms (sea perceptions and rapid fall in the availability of grasses and mangroves) and several of land based natural resources, the scientists have fungus and an array of microbes (bacteria and shifted their research to marine environment virus). Marine organisms are used as nutritious which has been found as the hidden ground for a foods, animal feed, ornamental and recreational plethora of bio-molecules which can be used for items and also as potential source of marine discovery of new drugs. In fact, over 7000 natural natural products in health care since ancient times. products have been isolated from marine organisms2 so far and this number is increasing Benthos in the sea, live in most harsh and with addition of new products every day. The hostile physical environment being exposed to bioactive compounds having pharmaceutical extreme conditions of temperature, pressure, application were mainly derived from some salinity and often hypoxia and anoxia like microbes8-12, seaweeds4, 13-16, ascidians17,18 and situations. They are also susceptible to stiff sponges19-21. In addition, some valuable products competition for space, food, mate as well as from salmon and shark and lysate from the microbial infections. Since there is almost no Limulus had also contributed significantly to the scope for physical protection to escape from pharmaceutical industries22-24. Several products different hazards, they adapt themselves through with nutritional and pharmaceutical value such as complex biochemical processes and physiological Poly Unsaturated Fatty Acids (PUFA), β-carotene mechanisms. Synthesis of secondary metabolites etc.25 are now available in the racks of medical is their unique ability that helps them to protect shops and some more are in pre-clinical and against the ill effects of environmental hazards clinical trials. The recent research findings8-25 and microbial infections and many of these are, have further shown that many more species of off late found as promising source to meet the 5 marine organisms, particularly the molluscs, stand human health care demand . as a prospective source of valuable bioactive Exploration and exploitation of sea based compounds with great potential for new leads. resources have witnessed a paradigm shift in 6,7 Molluscs constitute an important group of recent years . The rapid increase in human in marine hydrosphere representing 23% population, change in their life style and climate of all the organisms. Since majority of these live change impacts have propelled the origin and

962 INDIAN J MAR SCI VOL 44, No.7, JULY 2015 in harsh and hostile intertidal rocky shores, anti-cancer, anti-inflammatory, anti-microbial mudflats and shelf zone exposed to a series of properties are discussed here. physical and chemical stresses, they are susceptible to wounds and damages caused by Anti-cancer compounds inter-species and intra-species competitions and Cancer is one of the very painful and deadly microbial attacks. These organisms therefore have diseases of public concern worldwide. Cases of the capability to adapt themselves and overcome cancer are on stiff rise causing several deaths different kinds of stress with the synthesis of every year. The World Health Organization secondary metabolites possessing immunological (WHO) has projected the cancer related deaths to 26 property and anti-microbial activity . A about 12 million by 2030, while American Cancer neurotoxin, having analgesic properties making it Society has projected 27 million new cancer cases 1000 times more potent than morphine without leading to 17.5 million deaths by 2050. Despite any side effects isolated from gastropod Conus tremendous developments in science and 27,28 magus shows the uniqueness of secondary technology, no effective medicine could be metabolites extracted from cone shells. Research developed so far for treatment of cancer. Present findings have further delineated the presence of cancer treatment is limited to surgical intervention many other secondary metabolites in molluscs that involves removal of infected body part and having anti-oxidant, anti-inflammatory, anti- application of chemotherapeutic drugs and 29-37 microbial and anti-tumour properties . In fact, radiation therapy to destroy and inhibit the 38 39 molluscan origin alkaloids , carotenoids and proliferation of cancer cells. None of these 40 conotoxins have been tested successfully for treatments actually cure cancer, but mostly only their strong bioactive characteristics. However lengthen the lifespan of a patient. Again all these studies pertaining to drug-discovery from them treatments, especially the chemotherapy and 41-44 remains under explored . radiation therapy are associated with many life Present study consists the current status of the threatening side effects. Therefore stride has been exploration and exploitation of bioactive made to trace new compounds to combat cancer. compound source from marine molluscs with due It has been established that natural products are emphasis to Indian coasts. It is hoped that it more effective in cancer treatments with would provide basic insight in the field of minimum side effects. According to WHO 80% of pharmaceutical discoveries from the molluscs the world's population especially living in from the sea in order to battle with the growing developing countries rely on plant-derived health issues in new millennium. medicines41. Global statistics further suggests that about 60% of drugs approved for cancer treatment Marine and their significance are of natural origin and important among them are doxorubicin, daunomicin, bleomycin, Phylum mollusca were initially divided into 9 45 different classes of which two have been reported mytomicin-C, vincristine and vinblastine . as extinct. Of the seven extant classes, four have Oceans are now considered as treasure house of been labelled as major and three as minor phyla. bioactive compounds possessing anti-cancer (anti- The four major classes include Polyplacophora oxidant/cytotoxicity/anti-tumour) activity. During (Chiton, Katharina, Mopalia etc.), the last few decades, nearly 2500 new metabolites (Conch, Cones, Snails, Cypraea sp etc.), Bivalvia with promising anti-tumour property have been (Oysters, Clams, Mussels, Scallops etc.) and isolated and their effectiveness against cancer has Cephalopoda (Squids, Octopuses, Cuttlefish etc). been evaluated. The Food and Drug The three minor classes include Monoplacophora Administration (FDA) and those of the European (Neopilina), Solenogastres (Neomenia) and Agency for the evaluation of medicinal products Caudofoveata (Chaetoderma, Limifossor). Each have listed 113 drugs for cancer treatment during 1940 to 2010, in which only 2.65% are of marine of the extant molluscs supports some kinds of 46 economic activity. origin (Sawadogo et al., 2013) suggesting the need for more efforts, to utilise the marine Marine molluscs have been used in a variety resources in future. Marine molluscs stand as of ways; the most common being as a source of prospective candidates offering excellent food, ornaments and production of lime. A few opportunity to isolate anti-cancer compounds47. species act as scavengers in cleaning the Some important compounds of molluscan origin environment and pollution indicators (Mussel having convincing anti-cancer properties are watch programme). Of late, many molluscan given hereunder. species have been identified as superior source of secondary metabolites having wide range of Dolastatin 10 and Dolastatin 15: The linear pharmaceutical applications. Some important peptide Dolastatin 10 (Fig.1) and desipeptide compounds screened, isolated and tested for their Dolastatin 15 (Fig.2) have been isolated from the

PATI et al.: MARINE MOLLUSCS AS A POTENTIAL DRUG CABINET: AN OVERVIEW 963 sea hare Dollabella auricularia of Indian Ocean. Kahalalide F: Kahalalide F (Fig.3) extracted They are found to have promising anti-cancer from Hawaiian mollusca Elysia rufescens is found properties48. Dolastatin 10 is a pentapeptide to be good anti-cancer agent. It forms the largest having four structurally unique residues viz. and most active compound among the seven Dolavalin, Dolaisoleucine, Dolaproline and Peptides (six cyclic-A to F and one acyclic-G Dolaphenine along with Valine. It has been analogue peptides) isolated from E. Rufescens51. reported that Dolastine 10 interferes and disrupts The Kahalalide F developed by the Spanish cell division by mitosis49. Dolastatin 15 on the biopharmaceutical company Pharmamar is other hand, is a seven-subunit desipeptide considered as a novel anti-tumour drug candidate, structurally identical to anti-tubulin agent of which is in phase II clinical trial. It has shown Dolastatin 10 that could act as anti-mitotic agent. excellent anti-tumour activity in various solid According to Poncet50 (1999), both Dolastatin10 tumour models including colon, breast, non-small and Dolastatin 15 were in preclinical trial to use cell lung cancers and certain prostrate cancers. against breast and liver cancers, solid tumours and Kahalalide F could cause oncosis in cancer cells some leukaemia. Their significant inhibition by lysosomal induction and cell membrane property of mitotic cell division suggested that permeabilization. In addition it also inhibits the they can effectively target cancer cells. expression of certain specific genes that are involved in DNA replication and cell proliferation O H and thus the compound could inhibit tumour N N N H 52 N spreading and growth . N N O H S O O O O Keenamide A: Keenamide A is a new cytotoxic cyclic hexapeptide (Fig.4) isolated from the marine mollusc Pleurobranchus forskalii. It has Figure 1. Dolastatin-10 exhibited significant activity against the P-388, A- 549, MEL-20, and HT-29 tumour cell lines53. Thus it could also be a potential anti-cancer O N H biomolecule of molluscan origin. H O Spisulosine ES-285 N : The Spanish Pharmamar H O O group has isolated the potent anti-proliferative H O O N alkyl amino alcoholic compound (Fig. 5) namely N H Spisulosine ES-285 from the Arctic surf clam, O H Spisula polynyma54. This bioactive compound has O O H N intriguing mechanisms of action which is now in N H the phase I clinical evaluation. The molecular target of this molluscan alkyl amino alcohol compound is Rho (GTP-bp) 55. Figure 2. Dolastatin-15 Alkaloids: Alkaloids such as Lamellarins, a family of hexacyclic pyrrole alkaloids obtained from marine molluscs have shown promising anti-

Figure 3. Kahalalide-F

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Anti-inflammatory and Analgesic agents Inflammation is the complex biological response of vascular system which arises as the end product of oxidative stress. It is associated with over 100 different diseases such as arthritis, asthma, Alzheimer's diseases, allergies, cancer, dermatitis, heart and coronary diseases, Parkinson’s diseases etc, which could occur due to physical trauma, nutritional deficiency and environmental pollution. It is usually associated with pains and other sufferings requiring immediate medication. Inflammation control in fact always remains as hot topic in pharmaceutical Figure 4. Keenamide A and medical research. The treatment regimens of

an inflammatory disorder include usage of anti-

Figure 5. Spisulosine (ES-285) tumour activity acting as potential cytotoxic inflammatory agents as well as pain killers. All agents56. Perusal of literature further suggest that most all the anti-inflammatory and analgesic the alkaloids can induce apoptotic cell death drugs, either steroidal or non steroidal candidates through multi-target mechanisms including the available in the market today, have severe side 61 inhibition of topoisomerase-I, interaction with effects . Therefore importance has been laid to DNA and directly effecting the mitochondria. search for new natural anti-inflammatory and Some recent reports57 suggest that lamellarins analgesic ingredients which could provide better inhibit several protein kinases such as cyclin- relief with minimal side effects. Great progress dependent kinases, dual-specificity tyrosine has been made in the last 30 years towards phosphorylation activated kinase-1A, casein understanding the neural substrates of pain relief kinase-1, glycogen synthesis kinase-3 and PIM-1 and identifying novel molecular targets for anti- relevant to cancer. inflammatory and analgesic drug development. A series of bioactive compounds with promising Other Compounds: A depsipeptide namely anti-inflammatory and analgesic properties have Turbostatins 1-4 , derived from the Asian marine been identified and isolated from seaweeds, mollusc stenogyrus found to have potent marine bacteria, invertebrates, tunicates and anti-cancer property and thus it can be trapped in 58 37 vertebrates including fishes. Some marine future studies . Benkendorff et al. (2011) have molluscs have also found to possess secondary found that egg mass extracts of the Australian metabolites with significant anti-inflammatory muricid Dicathais orbita induce necrosis in HT29 and pain relaxing activity. Chellaram and colorectal cancer cells and induces apoptosis in Edward30, (2009) observed that 100% acetone Jurkat cells. This suggests that extracts extract fraction of the gastropod, Trochus have strong biomedical potential in developing tentorium exhibited promising anti-inflammatory natural therapy for treatment of neoplastic activity on albino rats. In an another study same Ulapualide-A tumours and lymphomas. , a authors have experimented taking 100% acetone macrolide isolated from nudibranch column purified extracts of gastropod, Drupa Hexabranchus sanguineus exhibits visible margariticola on albino rats, which too had cytotoxic activity against L1210 murine 30 59 shown potent anti-inflammatory property . leukaemia cells . One more anti-cancer molecule Recently the scientists of Central Marine Fisheries namely a 60 kDa protein was also obtained from Research Institute, India have isolated an effective the purple fluid of Aplysia dactylomela, which has anti-inflammatory ingredient namely Green exhibited anti-proliferative effect on human 60 Mussel Extract (GMe) from the green mussel cancer cell lines, especially on NB4 cell line . Perna viridis that used to develop Cadalmin TM The foregoing discussions show that several to combat arthritis. Earlier, Whitehouse et al.62 potent and important cancer therapeutic (1997) have investigated the anti-inflammatory compounds can be derived from marine molluscs. activity of the oil extracted from the freeze-dried

PATI et al.: MARINE MOLLUSCS AS A POTENTIAL DRUG CABINET: AN OVERVIEW 965 powder of NZGLM (Lyprinol™) in adjuvant-induced polyarthritis and collagen-induced arthritis in rats. Research findings have shown that the venom containing predatory cone snails offer excellent opportunity for obtaining anti- inflammatory ingredients from nature. Conopeptides are small (10– 35 residues) neurotoxin products derived from venoms of the Conus sp with solution structures and stabilized by a high density of cysteine residues63. According to Olivera64 (1999), these peptides take part in the defence, prey capture and some other biotic interactions of the concerned organism. Conotoxins of the cone species are neurotoxins of low molecular weight which has pain Figure 5. Spisulosine (ES-285) reducing property. Livett et al.43 (2004) had prospects. Based on their characteristic features described the cone toxins as potential anti- these peptides have been classified into several inflammatory natural ingredients stating that the groups. Some of the more important toxins synthesized by several marine cone snails Conopeptides discovered and used in drug yield numerous structurally and functionally discovery exercises are given in Table-1. diverse compounds which can provide a wide The above cited examples and the discussions range of therapeutic applications. They consist of made thereon clearly show that marine mollusca a mixture of peptides of relatively short strings of can be an ideal source of anti-inflammatory and amino acids and are rich in disulfide bonds. The analgesic ingredients in future. The level of organisms utilize these compounds in pacifying research in India in context to exploitation of their prey before immobilizing and killing it. The marine molluscan resource to derive anti- first marine drug approved in the United States for inflammatory and some compounds is mostly the treatment of chronic pain in spinal cord injury limited to screening and isolation of a few was of molluscan origin. These toxins act at peptides. Conotoxins resources of India have not various locations in the sensory systems that been exploited satisfactorily and therefore it mediate pain, including the periphery is spinal and requires vigorous studies to exploit this wonderful higher CNS centres. The source of Prialt is peptide resource for societal benefit. Development marine snails of the genus Conus magus65. of a new drug under the brand name Cadalmin- TM from Perna viridis against arthritis can be Ziconotide (Fig. 6) is a synthetic derivative of taken as only land mark achievement till date. short peptide extracted from the venom of two predatory cone snails (Conus geographus & Anti-microbial properties Conus magus) has been approved by the U.S. Several infectious diseases in man are caused food and Drug Administration in December 2004, 66 by microbes and hence efforts have been made to under the brand name “Prialt” . Other develop anti-bacterial and immunological drugs to compounds from cone snails also are found to cure and prevent the occurrence and spread of have great potential to be highly effective drug 67 such diseases in recent decades. Many of these candidates against pain . A compound namely anti-microbial drugs are produced either using the AVC1 isolated from Australian cone Conus secondary metabolites isolated from organisms or victoriae proved to be effective in reducing post synthesized in the laboratory taking cues from surgical and neuropathic pains and recovery from their biochemical and physiological functions. nerve injury. The marine environment is rich with varieties During last decade several toxins have been of microbes. Hence the biota living there is bound identified, isolated and tested for their medicinal

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Table 1. Some analgesic Conopeptides, their sources and biological activity Classification Conotoxins Conus Species Biological activity Source/Reference α- conotoxins Vc1.1(ACV-1) C. victoriae Targets the nicotinic acetylcholine 68 RgIA C. regious receptors (nAChR) at nerves and muscles. Inhibitor of N-type Calcium Channel. Analgesic activity in animal pain model when delivered by injection. µ-Conotoxins µ GIIIA and GIIIB C. geographus Targets voltage-graded sodium 69 µ PIIIA C. purpurascens channels in muscles. The µ TIIIA C.tulipa mechanism of action is intrathecal μ-SmIIIA C. striatus, and intranervous pain. C. kinoshitai, C. magus, C. consors, C. catus

µ O-ConotoxinsMrVIA C. Marmoreus and MrVIB C. gloriamaris δ-Conotoxins GVIIIA Some Targets the inactivation of voltage 70 δ-Conotoxin-GmVIA molluscivorous dependent sodium channels and “δ” cone snails slows the inactivation of the sodium channel ω-Conotoxins MVIIA(Prialt) C. magus Affects the calcium channels 71 CVID(AM336) C. catus associated with nerve impulse transmission at the neuromuscular junction. Calcium channels are related to sensitivity to pain. κ-Conotoxins kO-conotoxin PVIIA Conus Inhibits voltage-graded potassium 70 kA- MIVA, SIVA, purpurascens channels, resulting in tremors. SIVB, mIVA, SmIVB, Cardiac reperfusion. PIVE, CcTx, and PIVF Conantonkins Contulakin-G(CGX- Conus NMDA-receptor antagonists,. 72 1160 Conantokin- geographus Targets Epilepsy, pain, stroke, G(CGX-1007) C. tulipa Parkinson’s disease C. radiatus Chi-conopeptide MrIA and MrIB(Xen- Conus Inhibit the norepinephrine 70 2174)a marmoreus transporter CONTRYPHANS Contryphan Vn C. ventricosus Targets Calcium channels 73 C. radiatus C. loroisii C. amadis to develop chemical adaptations to protect activity against the human pathogen Vibrio themselves from the microbial pathogens. cholerrae and Aeromonas hydrophila. They Decades of research have shown that marine (Santhi et al.83 2013) have also reported the organisms offer tremendous opportunity to presence of anti-bacterial and anti-fungal harvest anti-microbial substances as well as substances in the benzyl: methanol and methanol provide cues for their laboratory synthesis. extracts of deep water mollusca Babylonia Several compounds such as chlorinated zeylanica capable of inhibiting the growth of acetylenes, indole alkaloids, glycoproteins and pathogens like Salemonella typhie, Eschesia coli, peptides exhibiting anti-microbial activity have and Aeromonas hydrophila. been isolated from marine molluscs74-80. Recent 81 Bacterial and viral infections are directly observations by Kumaran et al. (2011) linked with the immune efficiency of the delineated that two species of marine molluscs susceptible organism. Anti-microbial peptides namely tissoti and Babylonia spirata (AMPs) therefore represent the most universal contain bioactive compounds, possessing strong immune effectors. The review of Li et al.84 (2011) anti-microbial properties against human have shown that several bivalves including pathogens Klebsilla pneumonia, Proteous Mytilus galloprovincialis, M. edulis, M. trossolus, mirabilis; fish pathogen Aeromonas hydrophila; Crassostrea virginica, Ruditapes philippinarum fungal pathogens Aspergelas niger, Kendida and gastropods like Biomphalaria glabrata, albicans and against bio-film microbes like 82 Haliotis discus hannai, H. discus discus, H. Micrococus sp. At the same time Santhi et al. laevigata form important source of AMPs. As (2011) have observed the presence of secondary many as 69 different types of AMPs have so far metabolites in deep water mollusca Tonna galea, been isolated from two major groups of molluscs that offers promising prospects for anti-microbial (Table. 2) and this number can increase if

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Table 2. Number of extant species of Molluscs and AMPs reported the presence of low molecular weight reported from them glycosaminoglycan in Amussium pleuronectus Class Estimated number Number of (Linn, 1758) that afforded considerable protection of species reported AMPs to the heart tissues challenged by cardio toxicity Polyplacophors 900 - 1,000 0 induced by isoproterenol. Two selective potassium channel blockers, namely κM- Gastropods 70,000- 103,000 8 conotoxin RIIIJ and κM-RIIIK has been purified from the venom of a gastropod Conus radiatus. Cephalopods 730- 900 0 The cardio-protective effects of κM-conotoxin RIIIJ and κM-RIIIK were assessed in a male Bivalves 12,000- 20,000 61 Wister rat’s heart model of ischemia/reperfusion. ΚM-RIIIK found to reduce the infarct size of the Scaphopods 400- 500 0 risk zone drastically, although it (κM-RIIIJ) did not exert any apparent cardio protective action89, Source: Li et al.84 (2011) 90. These instance and presence of metabolites in extensive research will extend to other groups. cones having affinity to specific ion channels as The above cited examples explain that marine seen in cone toxins suggests their effectiveness molluscs could be an important source of anti- towards their therapeutics uses controlling the bacterial substances and immunological peptides cardio vascular diseases. for development of new generation of therapeutic Conclusion agents to battle with several infectious diseases. Among different forms of life, molluscs form Cardiovascular protective compounds: a dominant group which provides lots of socio- Cardio Vascular Diseases (CVDs) are non- economic benefits, serving as source of food, communicable diseases which affect the heart, ornaments and home decorative items and shells blood vessels (arteries and veins) and blood as raw materials for lime production. In addition, circulation. These diseases constitute one of the several species have anti-microbial, anti-oxidant, major causes of human death and disability in the anti-inflammatory, anti-cancer, anti-tumour world today. The report of WHO has estimated properties offering tremendous opportunity to that human deaths due to CVDs was at 17.3 harness this resource for production of new drugs. million per year in 2008 sharing about 30% of The chemical adaptations of some species also total deaths caused by various diseases85. It has provide best cues for synthesis of new compounds been shown that over 80% of CVD deaths take to battle many diseases. Thus marine molluscs can place in low and middle income countries and stand as a competent source of secondary death rates due to CVD in high income countries metabolites and that could be of great therapeutic are reasonably low. The status report of WHO use in the new millennium. “Global atlas on cardiovascular disease Acknowledgement prevention and control” published on 19 September 201186 projected a sharp increase in Authors are thankful to the Head, Department human death reaching to 23.6 million per year by of Marine Sciences for encouraging and providing 2030 due to CVDs. Owing to such increasing facilities. Premalata Pati and Biraja Kumar Sahu incidences of mortality and disability by CVDs, wish to acknowledge the financial support by considerable emphasis has been laid to discover DST, Government of India, New Delhi. and manufacture cardiovascular protective compounds with a higher potency. References 1. Pomponi, S. A., The bioprocess-technological potential With application of modern technological of the sea, J. Biotechnol., 70(1999) 5-13 skill, efforts have been made to locate new cardio 2. Kijjoa, A and Sawangwong, P., Drugs and cosmetics protective agents from marine organisms from the sea, Mar. Drugs, 2(2004) 73-82 including marine molluscs. For instance, Sherief 3. Sima, P and Vetvicka, V., Bioactive substances with anti- et al.87 (2004) have studied the cardio protective neoplastic efficacy from marine invertebrates: Bryozoa, Mollusca, Echinodermata and Urochordata, World J. effects of cuttlefish (Sepia pharaonis) liver oil in Clin. Oncol., 2(2011) 362-366 isoproterenol administrating on rats. In another study, Sarvanan and Sanmugam88 (2010) have

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4. Mohapatra, L., Pati, P., Panigrahy, R. C and Bhattamisra, S. 26. Glinski, Z and Jarosz, J. Molluscan immune defense. K., Therapeutic health booster: seaweeds against several Arch. Immunol. Ther. Exp. (Warsz) 45(1997): 149-155 maladies, Indian J. Mar. Sci., 42 (2013) 538-546 27. Mayekar, T. S., Amod, A., Salgaonkar, J. M., Patil, K. 5. Sokolova, I. M., Apoptosis in molluscan immune defense, P., Chaudhari, A., Murkar, A., Salvi, S., Surve, D., ISJ, 6 (2009): 49-58 Jadhav, R and Tousif K., Marine biotechnology: 6. Schweitzer, J., Handley, F. G., Edwards, J., Harris, W. F., Bioactive natural products and their applications, Grever, M. R., Schepartz, S. A., Cragg, G., Snader, K and Aquafind, Aquatic Fish Database (2012) Bhat, A., Summary of the workshop on Drug 28. Ollivera, B. M., Conotoxin MVIIA: from marine snail Development, Biological Diversity, and Economic venom to analgesic drug. In: Fusetani N, ed. Drugs from Growth, J. Natl. Cancer. Inst., 83(1991) 1294-1298 the sea. Basel: Krager, (2000) 74-85 7. Rinehart, K. L., Antitumor compounds from tunicates, 29. Sanmugam, A., Subhapradha, N., Suman, S., Ramasamy, Med. Res. Rev., 20(2000) 1-27 P., Saravanan, R., Shanmugam, V and Srinivasan, A., 8. Baslow, M. H. In: Marine Pharmacology, (1969) Characterization Of Biopolymer “Chitosan” From The Williams & Wilkins Co. Baltimore, MD, 69-71 Shell Of Donacid Clam Donax Scortum (Linnaeus, 1758) 9. Bérdy, J., Bioactive microbial metabolites, J. Antibiot., and its Antioxidant Activity, Int. J. Pharm. Pharm. Sci., 58(2005) 1–26 4(2012) 460-465 10. Fenical, W., Chemical studies of Marine Bacteria: 30. Chellaram, C and Edward, J. K. P., Anti-inflammatory developing a new resource. Chemical Review, 93(1993) potential of coral reef associated gastropod, Drupa 1673-1683 margariticola, Indian Journal of Science and 11. Ebel, R., Secondary metabolites from marine–derived Technology, 2(2009) 75-77 fungi. In Frontiers in Biotechnology, In: Proksch, P., Mu¨ 31. Chandran, B., Rameshkumar, G and Ravichandran, S., ller, W.E.G. (Eds.), Frontiers in Marine Antimicrobial activity from gill extraction of Perna Biotechnology.Horizon Scientific Press, Norwich, (2006) viridis (Linn, 1758), Global Journal of Biotchnology and 73–143. Biochemistry, 4 (2009) 88-92 12. Keller, M and Zengler, K., Trapping into microbial 32. Charlet M., Chernysh S., Philippe, H., Hetru C., diversity, Nat. Rev. Microbiol., 2(2004) 141-150 Hoffmann J. A and Bulet P., Innate immunity, Isolation 13. Hashimoto, Y. In: Marine Toxins and Other Bioactive of several cysteine-rich antimicrobial peptides from the Marine Metabolites, Japan Scientific Societies Press, blood of a mollusc, Mytilus edulis, J. Biol. Chem., Tokyo, (1979), 369 pp 271(1996) 21808-21813 14. Faulkner, D.J., Marine natural products, Nat. Prod. Rep., 33. Chatterji, A., Ansari, Z. A., Ingol, B. S., Bichurina, M. 19(2002) 1-49 A., Sovetova, M and Boikov, Y.A., Indian marine 15. Tang, H. F., Yi, Y. H., Yao, X. S., Xu, Q. Z., Zhang, S. bivalves: Potential source of antiviral drugs, Current Y. and Lin, H.-W., Bioactive steroids from the brown Science, 82(2002) 1279-1282 Alga Sargassum carpophyllum, J. Asian Nat. Prod. Res., 34. Pakrashi, A., Roy, P and Datta, U., Antimicrobial effects 4(2002) 95-101 of proteins isolated from the marine mollusc Telescopium

16. Dhargalkar, V. K and Pereira, N., Seaweed: Promising telescopium, Indian J. Physiol. Pharmacol., 45(2001) Plant of the Millennium, Science and Culture, March- 249-252 April (2005), 60-66. 35. Schwartsmann, G., da Rocha, A. B., Berlinck, R. G. S 17. Davidson, B. S., Ascidians: producers of amino acid- and Jimeno, J., Marine organisms as a source of new derived metabolites, Chem. Rev., 93(1993) 1771-1791 anticancer agents, The Lancet Oncology, 2(2001) 221- 18. Urban, S., Blunt, J. W and Munro, M. H. G., 225 Coproverdine, a Novel, Cytotoxic Marine Alkaloid from

a New Zealand Ascidian, J. Nat. Prod., 65(2002) 1371- 36. Benkendorff, K., Brernner, J. B. and Davis, A. R., Indole 1373 derivatives from the egg masses of muricid molluscs, 19. Perdicaris S., Vlachogianni, T and Valavanidis A., Molecules, 6(2001) 70-78 Bioactive Natural Substances from Marine Sponges: New 37. Benkendorff, K., Mciver, C. M and Abbott, C A., Developments and Prospects for Future Pharmaceuticals. Bioactivity of the Murex homeopathic remedy and of Nat Prod Chem Res (2013), 1: 1–8 extracts from an Australian muricid mollusc against 20. Raj, S and Inbakandan, D., Anti cancer activity human cancer cells, Evidence-Based Complementary and prediction of secondary metabolites from marine sponge Alternative Medicine (2010), 2011: doi:10.1093/ ecam/ discodermia calyx: An in silico approach, Indian J. Mar. nep042 Sci., 42(2013) 653-658 38. Kumar, D and Rawat, D. S., Marine Natural Alkaloids as 21. Caralt, S. D., Bry, D., Bontemps, N., Turon, X., Uriz, M. anticancer agents. Opportunity, Challenge and Scope of J and Banaigs, B., Sources of Secondary Metabolite Natural Products in Medicinal Chemistry, (2011), 213- Variation in Dysidea avara (Porifera: Demospongiae): 268 The Importance of Having Good Neighbors, Mar. Drugs, 39. Matsuno, T and Tsushima, M., Carotenoids of shellfishes 11(2013) 489-503 X. Reductive metabolic pathways of echinenone and 22. Tachibana, K., Sakaitanai, M and Nakanishi, K., fritschiellaxanthin in the spindle shell Fusinus perplexus, Pavoninins: Shark repellent icthyotoxins from the Comparative Biochemistry and Physiology, 92 (1989) Defense Secretion of Pacific Sole, Science, 226(1984) 189-193 703-705 40. Imperial, J. S., Chen, P., Sporning, A., Terlau, H., Daly, 23. Tocher, D. R., Bell, J. G., MacGlaughlin, P., McGhee, F N. L., Craik, D. J., Alewood, P. F and Olivera, B.M., and Dick, J.R. Hepatocyte fatty acid desaturation and Tyrosine-rich Conopeptides Affect Voltage-gated K+ polyunsaturated fatty acid composition of liver in Channels, J. Biol. Chem., 283(2008) 23026 –23032 salmonids: Effects of dietary vegetable oil, Comp. 41. Adams, D. J., Alewood, P. F., Craik, D. J., Drinkwater, Biochem. Physiol. 130B (2001) 257-270 R. D and Lewis, R.J., Conotoxins and their potential 24. Joshi, B., Chatterji, A and Bhonde, R. Long-term in vitro pharmaceutical applications, Dev. Res., 46(1999) 219- generation of amoebocytes from the Indian horseshoe 234 crab Tachypleus gigas (müller), In Vitro Cell & Develop 42. Alonso, D., Khalil, Z., Satkunanathan, N and Livett, Biol- Animal, 38(2002), 255-257 B.G., Drugs from the Sea: Conotoxins as Drug Leads for 25. Kim, S. K. Marine Nutraceuticals: Prospects and Prospectives, CRC Press, 2013, pp 464.

PATI et al.: MARINE MOLLUSCS AS A POTENTIAL DRUG CABINET: AN OVERVIEW 969

Neuropathic Pain and Other Neurological Conditions, 59. Chattopadhyay, S. K and Pattenden, G A total synthesis Mini Reviews in Medicinal Chemistry, 3(2003) 785-787 of the unique tris-oxazole macrolide ulapualide A 43. Livett, B. G., Gayler, K. R and Khalil, Z., Drugs from the produced by the marine nudibranch Hexabranchus sea: conopeptides as potential therapeutics, Curr Med sanguineus. J Chem Soc Perkin 1(2000):2429–2454 Chem., 11 (2004) 1715-1723 60. Zandi, K., Farsangi, M. H., Nabipour, I., Soleimani, M., 44. Gurib-Fakim, A., Medicinal plants: traditions of Khajeh, K., Sajedi, R. H and Jafari, S. M., Isolation of a yesterday and drugs of tomorrow, Mole. asp of Med, 60 kDa protein with in vitro anticancer activity against 27(2006) 1-93 human cancer cell lines from the purple fluid of the 45. Hussain, Md., Fareed, S., Ansari, S and Khan, Md.S., Persian Gulf sea hare, Aplysia dactylomela, Afric J of Marine Natural Products: A lead for Anti-cancer, Indian Biotech, 6(2007) 1280-1283 J of Geo-mar Sci, 41:1(2012) 27-39 61. Rao, P. N. P and Knaus, E. E., Evolution of nonsteroidal 46. Sawadogo, W. R., Schumacher, M., Teiten, M. H., anti-inflammatory drugs (NSAIDs): cyclooxygenase Cerella, C., Dicato, M and Diederich, M., “A Survey of (COX) inhibition and beyond. J Pharm Pharmaceut Sci, Marine Natural Compounds and Their Derivatives with 11(2008):81-110. Anti-Cancer Activity Reported in 2011”, Molecules, 18 62. Whitehouse, M. W., Macrides, T. A., Kalafatis, N., Betts, (2013) 3641–3673 doi:10.3390/molecules18043641. W. H., Haynes, D. R and Broadbent, J., Anti- 47. Sawadogo, W. R., Schumacher, M., Teiten, M. H., Inflammatory Activity of a Lipid Fraction (Lyprinol) Dicato, M and Diederich, M., “Traditional West African from the NZ Green-Lipped Mussel, pharmacopeia, plants and derived compounds for cancer Inflammopharmacology, 5(1997) 237-246 therapy”, Biochem Pharmacol, 84(2013) 1225–1240 63. Norton, R. S and Pallaghy, P. K., The cystine knot 48. Yamada, K., Okija, M., Kigoshi, H and Suenaga K, structure of ion channel toxins and related polypeptides, Cytotoxic Substances from Opisthobranch Molluscs, in: Toxicon, 36(1998) 1573–1583 Drugs From The Sea; edited by, N. Fusetani and A.G. 64. Olivera, B. M., Conus venom peptides: correlating Karger, (Basel) (2000), pp. 59-73 chemistry and behavior. J Comp Physiol A 185 49. Bai, R. L., Pettit, G. R and Hamel, E., Binding of (1999):353–359 dolastatin 10 to tubulin at a distinct site for peptide 65. Molinski, T. F., Dalisay, D. S., Lievens, S. L and antimitotic agents near the exchangeable nucleotide and Saludes, J. P., Drug development from marine natural Vinca alkaloid sites, J of Biol Chem, 26(1990) 17141– products, Nat Rev Drug Discov, 8(2009) 69–85 17149 66. Joseph, B., Rajan, S. S., Jeevitha, M. V., Ajisha, S. U. 50. Poncet, J., The dolastatins, a family of promising and Jini,D.,Conotoxins: A Potential Natural Therapeutic antineoplastic agents. Curr. Pharm. Des., 5(1999) 139- For Pain Relief, Int J of Pharm and Pharmaceut Sci, 3: 162 2(2011) 1-5 51. Lopez-Macia, A., Jim nez, J. C., Royo, M., Giralt, E and 67. Park, Y., Mining invertebrate natural products for future Albericio, F., Synthesis and Structure Determination of therapeutic treasure, Nat Prod Com 6(2011) 1403–1408 Kahalalide F1,2, J of Americ Chem. Soc, 123 (2001) 68. Callaghan, B., Haythornthwaite, A., Berecki, G., Clark, 11398-11401 R. J., Craik, D. J and Adams, D. J., Analgesic alpha- 52. Hamann, M. T., Otto, C. S and Scheuer, P. J. conotoxins Vc1.1 and Rg1A inhibit N-type calcium Kahalalides: Bioactive peptides from a marine mollusk channels in rat sensory neurons via GABAB receptor Elysia rufescens and its algal diet Bryopsis sp, Journal of activation, J. Neurosci., 28(2008) 10943–10951 Organic Chemistry, 61(1996): 6594-660 69. Norton, R. S., µ-conotoxins as leads in the development 53. Wesson, K. J and Hamann, M. T. Keenamide A, a of new analgesics. Molecules, 15 (2010): 2825–2844 bioactive cyclic peptide from the marine mollusk 70. Lewis, R. J., Dutertre, S., Vetter, I and MacDonald, J. C., Pleurobranchus forskalii. J. Nat. Prod. 59 (1996): 629– Conus Venom Peptide Pharmacology, Pharmacol Rev, 631 64(2012) 259-298 54. Cuadros, R., Garcini, M. D. E., Wandosell, F., Faircloth, 71. Miljanich, G. P., Ziconotide: neuronal calcium channel G., Fernández Sousa, J. M and Avila, J., The marine blocker for treating severe chronic pain. Curr Med compound Spisulosine, and inhibitor of cell proliferation Chem., 11(2001) 3029–3040 promotes the disassembly of actin stress fibers, Canc. 72. Shen, G., Layer, R and McCabe, R., Conopeptides: From Lett, 152(2000) 23-29 deadly venoms to novel therapeutics. Drug Discovery 55. Thakur, N. L., Jain, R., Natalio, F., Hamer, B., Thakur, Today, 5(2000) 98–106 A. N and Müller, W. E. G., Marine molecular biology: 73. Sabareesh, V., Gowd, K. H., Ramasamy, P., Sudarslal, S., An emerging field of Biological Sciences, Biotech Adv, Krishnan, K. S., Sikdar, S. K and Balaram, P., 26(2008) 233-245 Characterization of Contryphans from Conus loroisii and 56. Andersen, R. J., Faulkner, D. J., He, C. H., Van Duyne, Conus amadis that target calcium channels, Peptides, G. D and Clardy, J., Metabolites of the marine 27(2006) 2647–2654 prosobranch mollusk Lamellaria sp., J of Americ Chem 74. Shaw, P. D., McClaure, W. O., Van Blaricom, G., Sims, Soc, 107(1985) 5492-5495 J., Fenical, W and Rude, J.. Antimicrobial Activities from 57. Baunbæk, D., Trinkler, N., Ferandin, Y., Lozach, O., Marine Organisms. In: Food-Drug from the Sea Ploypradith, P., Rucirawat, S., Ishibashi, F., Iwao, M Proceeding, Webber, H.H. and G.D. Ruggieri (Eds.). and Meijer, L., Anticancer Alkaloid Lamellarins Inhibit Marine Technology Society, Washington DC (1976) 429- Protein Kinases, Mar. Drug, 6(2008) 514-527 433

58. Pettit, G. R., Tang, Y and Knight, J. C., Antineoplastic 75. Fenical, W., New pharmaceuticals from marine agents. 545. Isolation and structure of turbostatins 1-4 organisms, Trend Biotechnol., 15 (1997) 339–341 from the Asian marine mollusk Turbo stenogyrus, J of Nat Prod, 68:7(2005) 974–978

970 INDIAN J MAR SCI VOL 44, No.7, JULY 2015

76. Anand, T. P., Rajaganapathi, J and Edward, J. K. P., 84. Li H., Parisi, M. G., Parrinello, N., Cammarata, M and Antibacterial activity of marine mollusc from Portonovo Roch, P., Molluscan antimicrobial peptides, a review region. Indian J. Mar. Sci., 26 (1997).: 206-208 from activity-based evidences to computer-assisted 77. Iguchi, S. M., Aikawa, T and Matsumoto, J. J., sequences, ISJ, (2011). 8: 85-97 Antibacterial activity of snail mucus mucin. Comp. 85. Global atlas on cardiovascular disease prevention and Biochem. Physiol. A: Comp. Physiol., 72(1982) 571-574 control. Geneva, World Health Organization, 2011. 78. Zhong, J., Wang, W., Yang, X., Yan, X and Liu, R. A., 86. Global status report on non-communicable diseases 2010. Novel cysteine-rich antimicrobial peptide from the mucus Geneva, World Health Organization, 2011. of the snail of Achatina fulica. Peptides 39 (2013) 1–5 87. Sherief, P. M., Joseph, S. M., Nair, J. R. and George, M. 79. Hubert F., Vander Knaap, W. P., Noël, T and Roch, P., C., Cardio protective effect of Cuttle fish liver oil in Cytotoxic and antibacterial properties of Mytilus isoproterenol administered rats. Int. Symp. on galloprovincialis, Ostrea edulis and Crassostrea gigas atherosclerosis, (University of Kerala, Trivandrum) (bivalve mollusks) hemolymph. Aqua. Living Res, abstract, (2004), 26 9(1996b) 115-124 88. Saravanan, R and Sanmugam, A., Preventive Effect of 80. Iijima, R., Kisugi, J and Yamazaki, M., A., Noble Low Molecular Weight Glycosaminoglycan from antimicrobial peptide from the sea hare Dobella Amussium pleuronectus (Linne) on Oxidative Injury and auricularia, Dev. Comp. Immunology, 27(2003) 305-311 Cellular Abnormalities in Isoproterenol-Induced 81. Kumaran, S. N., Bragadeeswaran, S and Thangaraj, S., Cardiotoxicity in Westar Rats. Appl. Biochem Biotech, Screening for antimicrobial activities of marine mollusks 1:162(2010) 43-51 Thais tissoti (Petit, 1852) and Babylonia spirata 89. Chen, P., Garrett, J. E., Watkins, M. and Olivera, B.M., (Linnaeus, 1758) against human, fish and biofilm Purification and characterization of a novel excitatory pathogenic microorganisms, Afric J of Microbiol Res peptide from Conus distans venom that defines a novel 5:24(2011) 4155-4161 gene superfamily of conotoxins, Toxicon, off J of the Int 82. Santhi, V., Sivakumar, V., Thilaga, R. D and Boriga, J.F., Soc on Toxinol, 52(2008) 139-145 Bioactive potential of Tonna galea (Linn, 1758) from 90. Chen, P., Dendorfer, A., Finol-Urdaneta, R. K., Terlau, H Gulf of Mannar, Glob J of Pharmacol. 5:3(2011) 130- and Olivera, B. M., Biochemical characterization of κM- 135 RIIIJ, a Kv1.2 channel blocker: evaluation of 83. Santhi, V., Sivakumar, V., Mukilarasi. M and Kannagi, cardioprotective effects of κM-conotoxins, J. Biol. A., Antimicrobial substances of potential biomedical Chem., 285(2010) 14882–14889 importance from Babylonia zeylanica. J of Chem and Pharmaceut Res, 5:9(2013) 108-115