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From the Sea to Anticancer Therapy

P. Russo*,1, C. Nastrucci1 and A. Cesario1,2
1 2

IRCCS "San Raffaele Pisana", Rome, Italy Thoracic Surgery Unit, Catholic University, Rome, Italy
Abstract: Discovery, isolation, characterisation and pre-clinical and clinical trials of plant- or animal-derived drugs displaying pharmacological activities continue to develop and enlarge. Cancer chemotherapy is one of the most promising areas for these drugs. Since a very long time, nature has been an attractive source of potential medicinal agents for human use. The deep sea is becoming a novel and potently appealing source for new drugs, as well as shallow waters. This interest is mainly related to the terrific chemical diversity found in the vast number of plants and animal species, as well as in the microbial world. During the evolution, a rich source of biologically active compounds is developed in the depths of the sea, often reflecting ecological adaptation. Most of them (toxins) are developed to allow survival and flourishing acting against predators and parasites. Recent progress in Scuba diving, hitech/biotechnological and procedural advances in structure clarification, organic synthesis and biological assay determined the characterisation and preclinical/clinical evaluation of novel anticancer drugs. The aim of this review is to provide a description of their discovery, mode of action and clinical application.

Keywords: Anti-cancer therapy, clinical trial, FDA-approval, EMEA-approval, marine compound, mechanism of action, pre-clinical trial, synthetic compound. "The great depths of the ocean are entirely unknown to us. Soundings cannot reach them. What passes in those remote depthswhat beings live, or can live, twelve or fifteen miles beneath the surface of the waters-what is the organisation of these animals, we can scarcely conjecture". Jules Verne, "Twenty Thousand Leagues Under the Sea" (PART 1 - CHAPTER II, PRO AND CON) [1]. INTRODUCTION The potential therapeutic effects of natural products have been recognised since ancient times. Thus, plants and their extracts have been employed for the treatment of different human diseases for millennia, and their use has been documented in most ancient archaeological sources. When in September 1991, in the Tyrolean Alps (Italy), the well-preserved body of tzi, the Iceman (the Similaum man old of 5,300 years) was discovered, some medicinal herbs were found in his personal effects. These herbs probably were used to treat the parasites found in his intestines [2]. Although morphine was extracted from opium only in 1817 by Frederick Serturner (17831841), ancient civilisations in the Persia, Egypt, and Mesopotamia cultivated the poppy plant [3]. Thus, in the oldest medical text, written in Mesopotamia around 2,600 years before modern era, Papaver somniferum was included in a list of approximately 1,000 plants and plant-derived substances [4]. The isolation of morphine from opium - the first isolation of a natural product was a seminal event in the development of pharmacology as an independent discipline. The modern oncology utilizes different important plant-derived anticancer drugs, such as taxol or vincristine [5]. The newest tendencies in natural drug discovery highlight the marine ecosystem as a source of novel chemical entities for new leads in the treatment of cancer [4]. With the ocean covering 70% of the Earths surface, and with the uniqueness of the environmental conditions present in the oceans, the ocean can be considered a very promising source of natural drugs or synthetic derivatives for the future [6]. Marine life, during evolution, developed a large number of organic compounds that are not directly involved in their normal growth, development or reproduction. Essentially, the functions of these compounds (toxins) are predator deterrence, prevention of fouling, inhibition of overgrowth, and protection from ultraviolet radiation [7]. The richest sources of these toxins are soft-bodied and mainly sessile organisms, such as sponges, cnidarians, sea slugs, and tunicates, that lack physical defence against their predators, and use, for their chemical defence, some cytotoxic secondary metabolites [6]. Since these compounds are released into the water and therefore rapidly diluted, they have to be characterized by an outstanding potency to retain their efficacy. According to a recent review the described chemical diversity of the sea totalled 18,552 marine natural products (MNPs), from 27 marine phyla, dominated by sponge (35.6% total) and cnidarians-derived (18.6% total) compounds [8]. The discovery/isolation of C-nucleosides from the Caribbean sponge, Cryptotheca crypta, provided the basis for the synthesis of cytarabine [1- -arabinofuranosylcytosine (Ara-C)], the first marinederived anticancer agent for clinical use that is one of the most effective chemotherapeutic agents in the treatment of acute myeloid leukaemia (AML) since the 1960s [9]. Moreover, one of its fluorinated derivatives, gemcitabine, is used, for an example, as first line, in combinations with other drugs, in the advanced non-small cell lung cancer (NSCLC) [10]. Starting to the fifties the isolation and identification of marine natural products with anti-cancer properties flourished [11]. This "explosion" is mainly related to the progress made by the development and implementation of Scuba diving techniques and submersibles that allow the pharmacological exploration of the seas to collect the source organisms. There are currently two Food and Drug Administration (FDA)approved drugs in the U.S. Pharmacopeia, namely cytarabine [Cytosar-U1, Depocyt1, (Jun 17 1969) [11]) and Eribulin [Halaven [12], recently approved also by the European Agency for the Evaluation of Medicinal Products (EMEA) [13] in cancer treatment. Trabectedin (Yondelis1) is approved by EMEA in cancer treatment [14], and is completing key Phase III studies in the U.S. for approval. It was estimated that 118 MNPs are in preclinical trials, 22 MNPs in clinical trials and 3 MNPs in the market. MNPs in preclinical trials derived from 16 phyla, namely Porifera (39.0% total), Chordata (9.7%) and Ascomycota (9.3%). MNPs in clinical trials were derived from 8 phyla, namely Porifera (34.1% total), Mollusca (18.2%), Chordata (13.6%) and Proteobacteria (13.6%). MNPs in the market were derived from 2 phyla, with 2 compounds (Cytarabine and Halaven) from Porifera and 1 compound (Yondelis) from Chordata [8]. This review will briefly provide details of two FDA-approved drugs and for the one EMEA- approved, information concerning their discovery, mode of action and clinical application. Moreover,
2011 Bentham Science Publishers Ltd.

*Address correspondence to this author at the IRCCS "San Raffaele Pisana", Via di Valcannuta, 247, I-00166 Roma, Italy; Tel: +39 348 3339704; Fax: +39 06 52255668; E-mails: patrizia_russo@hotmail.it, patrizia.russo@sanraffaele.it 0929-8673/11 $58.00+.00

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the reviewed drugs currently under Phase II or III such as Plitidepsin (Aplidin), Eribulin mesylate (E7389), ILX651 (synthadotin or tasidotin), an orally active third-generation Dolastatin 15 analogue, and Bryostatin-1 have been reviewed. Briefly details of the recently discovered compounds, such as Spisulosine, Discodermolide, Salinosporamide, or a marine lipid extract from the New Zealand green-lipped mussel (Perna canaliculus), which entered in Phase I studies, will be reported. Moreover, two compounds, such as Neovastat and Zicotinide will also be reviewed here. CYTARABINE (ARA-C, CYTOSAR-U; TARABINE PFS) In 1945 Werner Bergmann, a young organic chemist, collected some unidentified sponges species in the shallow waters off Elliot Key, Florida [15]. The same species of sponge was also found in the waters off Bimini Islands in the Bahamas (3-60 m under water). The taxonomist de Laubenfels named the sponges Cryptotethia crypta [15]. After boiling in acetone, a crystalline material, similar to but not thymidine, was isolated. It was named spongothymidine, but, according to its chemical structures, its scientific name is "3beta-D-arabofuranosylthymine [16]. Spongothymidine differs slightly from thymidine, a DNA base, thus there is a hydroxyl (OH, alcohol) group instead of a hydrogen (-H) at the C-2 carbon position of the molecule (Fig. 1). At the time of Bergmann's discovery the study of DNA structure and replication was in the initial stages (in 1953 Watson and Crick published the DNA structure [17]) as well as the anticancer therapy (in 1955 the United States Congress created a National Cancer Chemotherapy Service Center at the National Cancer Institute (NCI) [18]). Having observed that malignant cells grow out of control, it was supposed that a strategy to kill them might be blocking their cell (DNA) replication. Therefore, some scientists started to design or find compounds able to interfere with the replication of DNA. At that time, the approach involved changing in the base part of the nucleoside, whereas the sugar (deoxyribose) remained intact. Then, spongothymidine was discovered and captivatingly contained nucleosides with a modified sugar instead of a modified base. This led medical researchers to design nucleosides with changed sugar moieties. One such nucleo-

side was cytosine arabinoside (cytarabine or Ara- C; Pfizer U.S. Pharmaceuticals Group) [19]. The seminal work of Seymour Cohen highlighted its antitumor activity, thus, one of his papers is considered a Citation Classic [20]. Then, Howard Skipper translated Ara-C from the laboratory bench to the bed treating childhood ALL [21-23]. Recently FDA approved intrathecal liposomal cytarabine (ITlipAC) in relapsed or refractory infant and paediatric leukaemia [24]. More analogues have been designed, synthesized, and found to be active against cancer cells. A difluorinated analogue of deoxy-cytidine, namely gemcitabine (Gemzar, Fig. 1) [25] is currently considered as the first line treatment for advanced pancreatic [26] and gastrointestinal cancer [27] as well as in advanced NSCLC [28] and advanced breast cancer [29]. Discodermolide (XAA296A) The light sensitive compound, Discodermolide discovered in 1987 at the Harbor Branch Oceanographic Institution by the Gunasekeras group was isolated from the Caribbean marine sponge Discodermia dissoluta living at 140 m. (330ft) in the sea [30]. This drug is a macrolide (polyhydroxylated lactone) and a member of the polyketides class of compounds, binding and stabilizing the microtubules of target cells and Salisporamide A, inducing the G2/M stage in the cell cycle, thus arresting cell division and causing apoptosis in many cancer cell lines [31]. In addition to anticancer properties, discodermolide possesses immunosuppresive and cytotoxic activity. It was licensed by Novartis Pharma AG for commercial development in 1998 and underwent Phase I human clinical trials, at the beginning showing promising anticancer properties, particularly for pancreatic cancer and other multi-drug resistant cancers [32]. Treatment with discodermolide provokes late activation of caspase-3 and -8 and a cleavage of poly(ADPribose)polymerase (PARP) in NSLCS cells [33]. Moreover, this treatment causes an efflux of cytochrome c from the mitochondria, however, neither Bcl-2 overexpression nor FADD-negative cells or inhibition of caspases managed to prevent

Fig. (1). Spongothymidine and its derivatives. Adapted from: [136] sponge; [137] chemical structure thymidine, spongothymidine, Ara-C; [138] chemical structure Gemtamicine.

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cells from apoptosis [33]. Additionally, release of cathepsin b (not caspase activation) appears to cause cell death induced by discodermolide because the inhibition of cathepsin b prevents NSLCS cells from apoptosis [33]. These apoptotic features suggest that an apoptotic cascade is involved in mediating the cytotoxic effects of discodermolide. The effects of discodermolide were promising in murine tumour models, however the pharmaceutical company Novartis withdrew it from Phase I trials because of lack of efficacy and cytotoxicity (mild-to-moderate toxicity from 0.6 mg/m2 to 19.2 mg/m2) in humans [34], nevertheless it is still considered potentially useful in combinatory drug therapy. Salinosporamide A (NPI-0052) Another molecule Salinosporamide was isolated in 1991 by Fenicle and Jensens at the Scripps Institution of Oceanography (SIO; University of California, San Diego) [35], being discovered from a cultured deep water actinomycete, Salinispora tropica, the first to be identified as a marine bacteria seawater-requiring [35]. It shows cytotoxic effects in tumour cells and induces apoptosis in cells resistant to protease inhibitors, such as bortezomib. Salinosporamide A is a proteasome inhibitor, which inhibits the activity of proteosomal enzymes like chymotrypsin and trypsin but also activates caspase-8 and 9. It seems, however that Salinosporamide A apoptotic pathway differs from the bortezomid pathway because it does not require signalling via Bax and Bak [36]. The authors believe that the differences observed in the induction of apoptosis may be a reason why bortezomib-resistant cells are sensitive to treatment with Salinosporamide A [36]. In normal lymphocytes and stem cells derived from bone marrow, Salinosporamide A also showed a lower cytotoxicity when compared to bortezomib [36]. Finally, Salinosporamide A is undergoing Phase I clinical trials for the treatment of relapsed and refractory multiple myeloma [37]. The material used for preclinical and clinical evaluation against drug resistant multiple myelomas, to date is obtained by fermentation and not by chemical synthesis [reviewed by 35, 38]. Bryostatin 1 (NSC339555) The bryostatins belong to a group of 20 novel macrocyclic lactones originally isolated from a Californian population of the fouling community marine bryozoan Bugala neritina (Bugulidae) by the group of Pettit in 1983 [39] and it is one of the best studied compounds of this kind. It appears to have a range of properties, including anti-cancer, anti-tumour, immunostimulant bioactivity (including immunomodulation and stimulation of haematopoietic progenitor cells and to activate T-cells). The production of Bryostatin 1 is carried out to date by cultivating Bugala neritina, as a complete chemical synthesis has not been accomplished. The molecular site of action was discovered and Bryostatin 1 was found to bind to protein kinase C with high affinity, perhaps the key for the anticancer and immunostimulating activities observed. In particular, Bryostatins mode of action consists in binding to the regulatory domain of the protein kinase C (PKC) competing with natural PKC ligands like phorbol esters [40], then bryostatin 1 induces PKC activation by autophosphorylation and translocation to the cell membrane [41]. Bryostatin 1 appears to prompt different effects on tumour cell lines, such as inhibiting proliferation, inducing final differentiation and causing apoptosis [42]. In particular, Bryostatins were tested in combination with other cytotoxic agents, particularly because Phase II studies involving single agents have shown minimal activity and as PKC activation could cause chemoresistance. Bryostatin 1 induces phosphorylation of the anti-apoptotic protein Bcl-2, thereby inactivating it [43], taken as a single compound which shows weak apoptotic effects, but in a combination therapy becomes an interesting agent. For example, Bryostatin 1 combined with paclitaxel was found to synergistically increase the upregulation of caspases induced by pacli-

taxel, even in cells overexpressing the anti-apoptotic protein Bcl-xL [44]. Several Phase II studies have been occurred to date, in particular, Phase II study of bryostatin-1 (NSC 339555) and paclitaxel in patients with metastatic or unresectable locally advanced adenocarcinoma of the stomach or gastroesophageal junction, the combination of bryostatin-1 and paclitaxel (weekly) was found to be active in patients with gastric and gastroesophageal adenocarcinoma (supported by NCI -National Cancer Institute- Contract No. T99-0103) [45]. Also in another Phase II trial, in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma, sequential paclitaxel followed by bryostatin-1 resulted in a better response rate than expected by paclitaxel alone [46]. However, a phase II study of bryostatin-1 and paclitaxel in patients with advanced non-small cell lung cancer gave disappointing results, the drugs combination showed no significant clinical response but was associated with reproducible toxicity, particularly myalgia with no elevated serum cytokines, suggesting a non-inflammatory etiology of this toxicity [47]. It consistently appears, following several independent studies on the action of Bryostatin 1 for the treatment of intractable diseases, such as cancers, like leukaemia, melanomas, adenocarcinima, etc., with or without other compounds for a combined treatment whose most common side effect is myalgia i.e. muscle pain, but taken as a single therapeutic agent also demonstrates little efficacy in humans. Neovastat (AE-941) Neovastat is a standardized aqueous shark cartilage extract. Although this compound is not strictly derived from the deep sea, it is classified as a naturally occurring multifunctional antiangiogenic agent, blocking the formation of blood vessels. Essentially Neovastat prevents tumours form the formation of new capillaries in tumours, thereby depriving them of oxygen and the nutrients they need to grow, in fact both tumour growth and metastasis are dependent on angiogenesis [48]. Neovastat, administered orally, was evaluated for safety and efficacy in phase I and II clinical trials in patients with advanced lung cancer refractory to treatment, at the beginning with promising results for possible survival benefits, showing a dose-dependent increase in the median survival time [49]. More recently, however, a randomized Phase III trial, on patients with unresectable stage II NSCLC was published [50]. In this randomized, double-blinded, placebo-controlled Phase III clinical study, no activity of Neovastat is reported. Ziconotide (Prialt) Ziconotide is a synthetic form of peptide extracted from the venom of predatory tropical cone snails Conus magus, living under 2000 m in the sea [51]. Generally, the pharmacological properties of conopeptides are interesting, among those the -conotoxin MVIIA (Ziconitide, Prialt) has obtained an approval as an analgesic drug. Essentially, Ziconotide, binding to presynaptic N-type calcium channels, reversibly blocks their activity reducing the release of excitatory neurotransmitter [52]. Ziconotide received FDA approval in December 2004 (Prialt1 is marketed by Elan Corporation, PLC [53] as an infusion into the cerebrospinal fluid through an intrathecal pump system and is currently used against severe chronic pain in patients with cancer or AIDS [54]. Ziconotide has also been approved by the EMEA [Doc. rif.: EMEA/772122/2009 EMEA/H/C/551]. Although the therapeutical importance of Zicotinide as anti-pain is undoubtful, it is however beyond the objective of the review (antineoplastic activity); thus its use in cancer therapy is mainly for palliative care and therefore included. Eribulin Mesylate (E7389) Eribulin mesylate (E7389, Halaven, Eisai Europe, Ltd.), a structurally simplified, synthetic analogue of the MNP Halichondrin B was recently approved by the U.S. FDA (November 15, 2010) to

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treat patients with metastatic breast cancer who have prior received at least two chemotherapy regimens for late-stage disease, including both anthracycline- and taxane-based chemotherapies [12, 55]. Very recently, on 20 January 2011, the EMEA approved Eribulin mesylate (Halaven) in monotherapy for the following indication: treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least two chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments" [13]. As highlighted by Nature in 2010:... It represents a hard-won victory for the total synthesis of natural products, a field of chemistry that, although still popular in academia, had gone out of fashion for many in the pharmaceutical industry" [56]. Complex marine natural products of the Halichondrin class were isolated by Uemura and Hirata from the western Pacific sponge Halichondria okadai [57], and later by Pettit et al. from the Comoros marine sponge Axinella-carteri [58]. Unfortunately, only miniscule amounts of Halichondrin B were obtained from its marine source. Thus, Halichondrin B was synthesized de novo [59], and this work led to the syntheses of multiple truncated analogues including the macrocyclic ketone analogue E7389 [60] (Fig. 2). E7389 is more potent than the parental compounds in interacting with tubulin. Both two compounds bind to tubulin and inhibited its assembly showing to be non-competitive inhibitors of vinblastine or Dolastatin 10 to tubulin, however, they did not induce an aberrant tubulin assembly reaction, which is the characteristic of both vinblastine (tight spirals) and Dolastatin 10 (aggregated rings and spirals) [61]. It is most likely, as molecular modelling studies suggested, that both drugs form highly unstable, small aberrant tubulin polymers, rather than the massive stable structures observed with vinca alkaloids and antimitotic peptides. Moreover, the binding models explained why the truncated form (E7389) is moderately more potent than the larger natural product [62]. Recently, it was reported that E7389 (Eribulin) is more potent than ER-076349 a

similar synthetic analogue (Fig. 2) [63]. It was suggest that Eribulin's in vivo superiority is related to its ability to induce irreversible mitotic blockade, correlated to persistent drug retention and Bcl-2 phosphorylation. Similar results arose with irreversible vincristine and reversible vinblastine, indicating persistent cellular retention as a constituent of irreversibility [63]. Eribulin entered in Phase II-III clinical trials. It seems particularly promising for pretreated patients, with several chemotherapic regimen, affected by locally advanced, recurrent, or metastatic breast cancer (Table 1) [64-67]. Trabectedin (YondelisTM, Formerly ET-743) Since 1986, the Developmental Therapeutics Program of the NCI acquired plants and marine organisms, through collection contracts performed in over 25 tropical and subtropical countries worldwide [68]. The project found that around 4% of the marine species examined (mainly animals) contained antitumour compound(s), a number close to that for terrestrial species (mainly plants). As a part of this program, an extract from the sea squirt Ecteinascidia turbinata was found, which in 1969, revealed anticancer activity [69]. Trabectedin (also known as ecteinascidin 743 or ET-743 or YondelisTM, PharmaMar in partnership with Johnson & Johnson Pharmaceutical Research & Development, L.C.C. J&JPRD-) is a tetrahydroisoquinoline alkaloid isolated from the marine tunicate Ecteinascidia turbinate (Fig. 3) with an exclusive mechanism of action, being able to bind at the minor groove of DNA and alkylate guanine at the N2 position, whereas most alkylating agents bind guanine at position N7 or O6 in the major groove [for a recent review see ref. 70]. As a consequence Trabectedin causes perturbation in the transcription of inducible genes (e.g., the multidrug resistance gene MDR1, HSP70 promoter, type I collagen) and interaction with DNA repair mechanisms (e.g., the nucleotide excision repair pathway) [71]. The transcription-coupled nucleotide excision repair-(TC-NER)-dependent activity of Trabectedin is similar to other anticancer agents that cause DNA-binding enzymes to kill cells. Interestingly, there are evidence of a

Fig. (2). Halichondrin-B and its derivatives. Adapted from: [139] sponge, [140] Chemical structure E7389, [141] Chemical structure ER-076349, [142] Chemical structure HalichondrinB.

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Table 1.

Eribulin in Phase II-III Clinical Trials

Tumour Phase Phase III (762 patients randomized 2:1) Phase III (1102 patients randomized 1:1 for Eribulin or capecitabine Phase II (87 patients) Schedules 1.4 mg/m i.v. infusion on days 1 and 8 of a 21-day cycle 1.4 mg/m2 i.v. infusion on days 1 and 8 of a 21-day cycle 1.4 mg/m2 i.v. infusion on days 1 and 8 of a 28-day cycle 1.4 mg/m2 i.v. infusion on days 1 and 8 of a 21-day cycle 1.4 mg/m2 on days 1 and 8 i.v. every 21day cycle. Activity with manageable tolerability [65]
2

Evaluation Conclusion Active Recommended dose reductions Ongoing

Ref. [64]

Extensively pretreated patients with locally recurrent or metastatic breast cancer.

Extensively pretreated patients with locally recurrent or metastatic breast cancer.

[64]

Metastatic breast cancer previously treated with an anthracycline and a taxane.

Locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine. Metastatic or recurrent squamous cell carcinoma of the head and neck.

Phase II (269 patients) Phase II (29 male, 11 female. Thirty-three patients (83%) with metastatic disease)

Efficacious in a population of extensively pretreated patients

[66]

No clinically significant activity

[67]

Fig. (3). Yondelis. Adapted from: [143] Chemical structure Yondelis, [144] Tunicate. correlation between mutations at the TC-NER system and the tendency to develop cancer [72]. The TC-NER machinery, like some chemotherapeutic agents, is implicated in the repair of adducts derived by alkylating agents. Trabectedin requires an efficient TCNER system to induce cytotoxicity in human cancer cell lines [70] and this correlation suggests a potential for combined therapy with platinum salts [70]. Trabectedin is specifically active against cells that are in G1 phase, making it a unique drug since other DNAalkylating agents are typically active on cells undergoing DNA synthesis [73]. This property makes Trabectedin a good candidate for antineoplastic activity. The Committee for Medicinal Products for Human Use concluded that Yondeliss benefits are greater than its risks and recommended that it be given marketing authorisation. Yondelis has been authorised under Exceptional Circumstances. Because the numbers of patients with soft-tissue sarcoma and ovarian cancer are low, the diseases are considered rare, and Yondelis was designated by EMEA an orphan medicine (a medicine used in rare diseases) on 30 May 2001 (for soft-tissue sarcoma) and on 17 October 2003 (for ovarian cancer) [74]. Also the U.S. FDA on October 7, 2004, granted orphan drug status to Yondelis to treat soft tissue sarcomas [75]. A recent work states that Trabectedin is a potentially cost-effective treatment of metastatic soft tissue sarcoma) patients [76]. Development in patients with other malignancies, such as breast and ovarian carcinoma, is currently ongoing [77-79]. However, in July 2009 FDA rejected Yondelis (in combination) to treat ovarian cancer [80]. AplidinTM (Plitidepsin) Plitidepsin (AplidinTM, PharmaMar USA Inc.) is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans currently obtained by chemical synthesis as a didemnin secondgeneration (Fig. 4). Different studies elucidated the mechanism of action of Plitidepsin. Briefly it causes modulation of: i. ii. iii. iv. v. vi. epidermal growth factor receptors non-receptor protein-tyrosine kinase SRC the serine/threonine kinases JNK, and p38 MAPK [81-83] Moreover induces: cell cycle arrest at G1-S and inhibition of protein synthesis [84-85] inhibition of the signal transduction process targeting the membrane-bound enzyme, palmitoyl thioesterase [86] inhibition of the vascular endothelial growth factor secretion [87-88]

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Fig. (4). Aplidin. Adapted from: [145] tunicate, [146] chemical structure Aplidin. vii. viii. inhibition of low molecular weight protein tyrosine phosphates [89] early induction of oxidative stress, activation of Rac1 small GTPase, Rac1 translocation to cholesterol-rich membrane domains and the later down-regulation of MAPK phosphatase 1 [90]. antimitotic activity. Dolastatin 15, a seven-subunit depsipeptide derived from Dolabella auricularia, common name "wedge sea hare", is a species of large sea slug, a marine opisthobranch gastropod mollusc in the family Aplysiidae [102]. In tasidotin the carboxyl-terminal ester group of Dolastatin 15 has been replaced by a carboxy-terminal tert-butyl amide (Fig. 5). Tasidotin, as well as its major metabolite tasidotin C-carboxylate (also called Ndesbenzylamino-cemadotin [103-104], inhibits mitosis without significantly depolymerising or disorganizing the spindle microtubules. Moreover, tasidotin inhibits weakly tubulin polymerization into microtubules in vitro and in contrast with other microtubuletargeted drugs it did not inhibit the growth rate. In contrast to stabilizing plus ends, tasidotin robustly suppresses dynamic instability at microtubule plus ends, whilst it weakly enhanced microtubule dynamic instability at minus ends. Interestingly, tasidotin Ccarboxylate is >10 times more potent than tasidotin. Thus, tasidotin may be considered a rather weak prodrug, while tasidotin Ccarboxylate, may be the more active intracellular form of the compound. The results imply that the principal mechanism of tasidotin is suppressing spindle microtubule dynamics [105]. Briefly, tasidotin induces a G2-M block suppressing spindle microtubule in treated cells that ultimately results in apoptosis [106]. At least three Phase I studies are being conducted [107-109]. Tasidotin displays a more favourable toxicity profile compared with other antitubulin agents (particularly the lack of severe cumulative neuropathy, pe-

Phase I programs reported that Aplidin induced neuromuscular toxicity, asthenia, skin toxicity, and diarrhoea, whereas no haematological toxicity was observed [91-92]. Since neuromuscular toxicity appeared similar to that described in the adult form of carnitine palmitoyl transferase deficiency type 2, a genetic disease treated with L-carnitine [93], it was concluded that Aplidin interacts with the carnitine system. Thus, L-carnitine was included to Aplidin trials to alleviate the neuromuscular toxicity and to allow a further dose escalation [94]. Table 2 reports Aplidin activity in Phase II trials. Briefly, Aplidin needs further evaluation in selected patients whereas it was completely ineffective in advanced or metastatic urothelium transitional cell carcinoma, relapsed or progressed SCLC and locally advanced or metastatic NSCLC [95-101]. ILX651 (Synthadotin or Tasidotin) ILX651 (Genzyme Corp., San Antonio, TX) is an orally active third-generation Dolastatin 15 analogue with microtubule-targeted
Table 2. Plitidepsin (Aplidin) in Phase II Trials
Tumour Relapsed-refractory multiple myeloma
2

Schedules 5 mg/m 3 h i.v. infusion every 2 weeks +/20 mg/day on days 1 to 4 of oral dexamethasone every 2 weeks 5 mg/m2 3 h continuous i.v. infusion every 2 weeks 5 mg/m2 3 h i.v. infusion every 2 weeks 5 mg/m2 3 h continuous i.v. infusion every 2 weeks 5 mg/m2 3 h continuous i.v. infusion every 2 weeks +/- L-carnitine 3.2 mg/m2 1 h weekly i.v. infusion 5 mg/m2 3 h continuous i.v. infusion every 2 weeks +/- L-carnitine

Conclusion Evaluation Single-agent has limited but reproducible activity in relapsed/ refractory multiple myeloma patients Activity observed after dexamethasone addition merits further study No objective tumour responses

Ref. [95]

Advanced or metastatic urothelium transitional cell carcinoma Unresectable advanced medullary thyroid carcinoma Advanced malignant melanoma

[96]

Limited clinical activity A minor degree of antitumor activity Further evaluation in combination schedules may be warranted. Some antitumor activity in selected patients Absence of antitumor activity Absence of antitumor activity

[97] [98]

Unresectable advanced renal cell carcinoma Relapsed or progressed SCLC Locally advanced or metastatic NSCLC

[99] [100] [101]

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Fig. (5). Halichondrin-B and its derivatives. Adapted from: [147] chemical structure Synthadotin, [148] chemical structure Dolastin-15, [149] mollusk. ripheral enema, and fatigue). Moreover, evidence for antitumour activity (a minor response in one patient with NSCLC, and a stable disease, lasting 11 months, in one patient with hepatocellular carcinoma) warrants further disease-directed evaluations. Phase II studies, conducted in melanoma, NSCLC, and hormone-refractory prostate cancer did not show sufficient efficacy to warrant further single agent development using intravenously (iv) route. Tasidotin will be investigated as an orally administered antineoplastic agent (as the hydrochloride salt) in patients with advanced, refractory cancer on the basis of new preclinical data [110]. ES-285 (Spisulosine) ES-285 (PharmaMar ES-285, PharmaMar USA Inc.), a natural analogue of the membrane phospholipid sphingosine isolated from the marine mollusc Spisula polynyma, is a sphingoid-type base which presents a long unsaturated alkyl chain (C18) and a 1,2aminoalcohol motif in an anti relationship (Fig. 6) [111]. Its primary mechanism of action has not yet been completely revealed. Since ES-285 induces cytoskeletal abnormalities and lost of actin stress fibres in exposed cells leading cell shape changes (from a bipolar and spindle-shaped appearance to a rounded contour [112], it was postulated that RhoA, a small GTP binding protein regulating actin stress fibres, was its main target. cDNA microarrays revealed that ES-285 treatment significantly alters the expression of a large number of genes including those involved in apoptosis, cell cycle, signal transduction and the actin cytoskeleton [113]. Moreover, Spisulosine, in prostate cells, induced apoptosis independently of the stress-related MAP kinases as well as of PPAR receptor, PI3K/Akt and classical PKCs, but, interestingly, induced de novo synthesis of ceramide, that in turn determines activation of PKC [114]. Until now only two Phase I studies have been completed. The first evaluated the safety, pharmacokinetics, pharmacogenomics, and efficacy of ES-285. In this phase I trial, ES-285 was administered as an i.v. infusion over 24 hours every 3 weeks. The maximum tolerated dose (MTD) was determined at 256 mg/m2, since 128 mg/m2 was considered the best tolerated. In this population of pretreated 28 patients, no objective tumour responses and no reductions in tumour markers were observed. However, stable disease was recorded in nine patients. Gene expression profiling by cDNA microarray in paired patient surrogate tissue samples (blood and skin biopsies), before and after 24-hour infusion of ES-285, showed that cell cycle genes were the most significantly overrepresented [115]. The second study, including thirty patients, considered as the MTD the concentration of 80 - 100 mg/m2/day with the liver enzyme elevations as dose limiting. Low antitumour activity was also observed [116]. GLMLE (Green-Lipped Mussel Lipid Extract, Lyprinol) GLMLE (Lyprinol; Pharmalink Marketing Services Pty. Ltd, Burleigh Heads, Queensland, Australia) is a marine lipid extract from the New Zealand green-lipped mussel (Perna canaliculus) (Fig. 7) obtained by supercritical fluid extraction [for more details of the technique see Ref. 117] of the stabilised mussel powder using liquefied carbon dioxide [118]. GLMLE contains a different number of lipids including sterol esters, triglycerides, free fatty acids (saturated and unsaturated), sterols and polar lipids. Free fatty acids (54%) and triglycerides (27%) constitute the predominant lipid classes of Lyprinol. Further investigation of Lyprinol by silver-ion thin layer chromatography and gas chromatography-mass spectrometry revealed a unique mixture of polyunsaturated fatty acids (PUFA) containing omega-3. Lyprinol exhibited strong inhibition of both COX-1 and COX-2, apparently, without selectivity of the two enzymes [119]. Lyprinol is also a potent inhibitor of the lipoxygenase (LOX) pathways, in particular, the 5-and 12-LOX enzymes [120] and induced apoptosis in cultured cell lines [121]. Despite the lack of clinical evidence, there was a significant media and public interest, supported only by preclinical results, that led to a considerable use by different patients [122]. Based on the publicity, the American Cancer Society continues an online information page on Lyprinol [123]. In 2002, an Australian study showed that Lyprinol, administered to thirteen patients with advanced prostate and breast cancer, did not shrink the tumours or reduce the levels of pain [124]. Recently (2010), a Phase I study in patients with advanced breast and prostate cancers did not reach the MTD and no objective tumour responses were observed [125]. This drug was included in the review to highlight, once more, the need of controlled human clinical trials for potential therapeutic agents, before widespread handling, based only on media conjectures.

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Fig. (6). ES-285. Adapted from: [150] Mollusk, [151] chemical structure ES-285. Finding a novel and potent bioactive natural product by random screening is, in itself, a big success in drug discovery. Indeed, a majority of these organisms live below the intertidal zones and often in the deep layer of the ocean under the thermocline at a depth of 1000 fathoms (1800 m) or more. These areas, called the benthic zone, are difficult to access and characterized by poor visibility, cold water and high pressure. Thus, it is extremely difficult to localize and identify the source of the compounds of interest. Moreover, the development of a new drug as well as the elucidation and evaluation of the molecule, usually requires extensive optimisation of conditions and large quantities of pure compounds exceeding those that are feasible to collect from a marine environment without affecting the natural population [126]. Furthermore, information on the ecological niche(s) of these organisms can be used to rapidly discover additional natural sources of the same or very similar compounds. Indeed, the employment of marine eukaryotes for large-scale production of drugs features several difficulties. They are largely due to the fact, that, in many cases, the eukaryotic organism is killed in the process of obtaining the bioactive material, and the majority of these eukaryotes cannot be cultured in laboratory, but need to be hand-picked by Scuba divers [127]. Finally, the sustainability of these organisms in nature might be compromised. The challenges of natural product research have resulted in a search for an alternative to bioactive product development. For instance high-throughput screening (HTS) of synthetic chemical libraries and the combinatorial chemistry might be used. Marine natural product extracts also show numerous problems for a modern drug discovery program such as : (a) presence of large quantity of inorganic salts, (b) chemical diversity reflecting unlike and seldom opposite pharmacological activities, (c) major presence of a nonselective compound possibly covering the activity of minor selective compounds, (d) concentrations below detection thresholds of minor compounds present in crude extracts. Fractionation strategies could effectively split the organic components from the inorganic salts and it would be useful to concentrate the active principal components. By having partially purified libraries, daughter plates can be easily generated for new screening programs [128]. However, in contrast to chemical libraries, marine compounds have been characterised by diversity and structural complexity that allow maximum selectivity and interaction with the target [129-130]. On the other hand, this complexity makes their chemical synthesis extremely difficult [131-133]. New analytical methods such as Ultra High Performance Liquid Chromatography (UPLC) coupled to high resolution mass spectrometers (MS), capillary probe nuclear magnetic resonance spectrometers, and Desorption Electrospray Ionisation Mass Spectrometry (DESI-MS) technique allow the process of natural product discovery from a limited samples [134]. In the area of cancer therapeutics, E. J. Corey and coworkers published the first enantioselective total synthesis of Ecteinascidin743 (Fig. 3) in 1996. Thus, Coreys brief total synthesis allowed the

Fig. (7). Lyprinol is a marine lipid extract from the New Zealand green-lipped mussel (Perna canaliculus) Adapted from: [152]. CONCLUSION Since 1945, marine organisms supplied natural products with a rich source of unusual metabolites [6]. The drug examples reported in this review showed that biologically different organisms from the sea continue to provide new small-molecule organic compounds with effective or potential anticancer activity. The introduction of some active agents such as Cytarabine, Eribulin mesylate or Yondelis helped to change the natural history of some types of human cancer. Moreover, these compounds offered a great opportunity to evaluate new and potentially relevant mechanisms of action (i.e. Yondelis). The understanding of the cellular/molecular pathway(s) supporting their antitumour activity and the analysis of their pharmacodynamic(s) might generate valuable information of the genes engaged in the sensitivity/resistance to these drugs. This approach might guide to the identification of patterns allowing adapted therapies. Although the mechanisms of action of these compounds are different, the ultimate antitumour effects are due to induction of apoptosis in cancer cells.

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1996. Thus, Coreys brief total synthesis allowed the use of this potent marine drug into advanced clinical trials [135]. Halaven (Eribulin mesylate) is the result of nearly 25 years of fights in the laboratory; it symbolizes a great victory in the total synthesis of natural products, a field of chemistry that, although well-liked by academia research, was considered unfashionable for many pharmaceutical industries. In conclusion, the importance of products from marine sources might be attributed to the various structures, intricate carbon skeletons, different and peculiar mechanisms of action and the ease in which human bodies would accept these molecules with minimal manipulation. The current tendency is to discover new precursor molecules from synthetic molecules, since it is more cost-effective and a less impactant option for the marine environment. The future will imply a close collaboration between academic research and the pharmaceutical industry to develop new drugs from chemical structures isolated from marine sources. Last but not least, environmental and conservation issues must be considered, as it is our duty to protect the sea, an invaluable source of living organisms and novel bioactive compounds, with countless properties, including those medically important, from inordinate human actions, such as disrupting fishing practices, like bottom trawling and from over exploitation and degradation of the coral reefs, as well as to point out that national and international laws should be able to protect the biodiversity and ecosystems of the seas. The development of new drug derived from the marine environment must always include a plan to supply enough compound for preclinical and clinical phases, especially when these drugs are found from living animals, invertebrates or algae that are found below the intertidal zone. ACKNOWLEDGEMENTS We apologize to the many contributors in this field whose work could not be cited here for space restrictions. ABBREVIATIONS Ara-C ALL AML EMEA FADD FDA iv LOX MNPs MTD NCI NSCLC PKC SCLC = 1- -arabinofuranosylcytosine = Acute Lymphoblastic Leukemia = Acute myeloid leukemia = European Agency for the Evaluation of Medicinal Products = Fas-Associated protein with Death Domain = Food and Drug Administration = Intravenously = Lipoxygenase = Marine natural products = Maximum tolerated dose = National Cancer Institute = Non-small cell lung cancer = Protein kinase C zeta = Small Cell Lung Cancer

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Revised: June 04, 2011 Accepted: June 05, 2011

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Received: March 04, 2011