From the Sea to Anticancer Therapy

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, hi-tech/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.

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Current Medicinal Chemistry, 2011, 18, 3551 -3562 3551
0929-8673/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.
From the Sea to Anticancer Therapy
P. Russo*,1, C. Nastrucci1 and A. Cesario1,2
1IRCCS "San Raffaele Pisana", Rome, Italy
2Thoracic Surgery Unit, Catholic University, Rome, Italy
Abstract: Discovery, isolation, characterisation and pre-clinical and clinical trials of plant- or animal-derived drugs displaying pharma-
cological 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 depths-
what 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 ar-
chaeological sources. When in September 1991, in the Tyrolean
Alps (Italy), the well-preserved body of Ötzi, the Iceman (the Simi-
laum 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 mor-
phine was extracted from opium only in 1817 by Frederick Ser-
turner (1783–1841), 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 approxi-
mately 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 vincris-
tine [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 Earth’s 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,
*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
and tunicates, that lack physical defence against their predators, and
use, for their chemical defence, some cytotoxic secondary metabo-
lites [6]. Since these compounds are released into the water and
therefore rapidly diluted, they have to be characterized by an out-
standing potency to retain their efficacy. According to a recent re-
view 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) com-
pounds [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 marine-
derived 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 fluori-
nated 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 develop-
ment and implementation of Scuba diving techniques and sub-
mersibles 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 [Cy-
tosar-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 ap-
proval.
It was estimated that 118 MNPs are in preclinical trials, 22
MNPs in clinical trials and 3 MNPs in the market. MNPs in pre-
clinical 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), Mol-
lusca (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 (Yon-
delis™) from Cho rdata [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,

3552 Current Medicinal Chemistry, 20 11 Vol. 18, No. 23 Russo et al.
the reviewed drugs currently under Phase II or III such as Plitidep-
sin (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, Sali-
nosporamide, 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 "3-
beta-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 dis-
covery 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. There-
fore, 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
Gunasekera’s 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 stabi-
lizing the microtubules of target cells and Salisporamide A, induc-
ing 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 prop-
erties, particularly for pancreatic cancer and other multi-drug resis-
tant cancers [32]. Treatment with discodermolide provokes late
activation of caspase-3 and -8 and a cleavage of poly(ADP-
ribose)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.

From the Sea to Anticancer Therapy Current Medicinal Chemistry, 2011 Vol. 18, No. 23 3553
cells from apoptosis [33]. Additionally, release of cathepsin b (not
caspase activation) appears to cause cell death induced by dis-
codermolide 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 No-
vartis 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 poten-
tially 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. Salinospo-
ramide A is a proteasome inhibitor, which inhibits the activity of
proteosomal enzymes like chymotrypsin and trypsin but also acti-
vates 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 be-
lieve 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 fermenta-
tion and not by chemical synthesis [reviewed by 35, 38].
Bryostatin 1
The bryostatins belong to a group of 20 novel macrocyclic lac-
tones originally isolated from a Californian population of the foul-
ing 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 Bry-
ostatin 1 is carried out to date by cultivating Bugala neritina, as a
complete chemical synthesis has not been accomplished. The mo-
lecular 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 syn-
ergistically 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 particu-
lar, Phase II study of bryostatin-1 (NSC 339555) and paclitaxel in
patients with metastatic or unresectable locally advanced adenocar-
cinoma of the stomach or gastroesophageal junction, the combina-
tion of bryostatin-1 and paclitaxel (weekly) was found to be active
in patients with gastric and gastroesophageal adenocarcinoma (sup-
ported by NCI -National Cancer Institute- Contract No. T99-0103)
[45]. Also in another Phase II trial, in patients with untreated, ad-
vanced gastric or gastroesophageal junction adenocarcinoma, se-
quential 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 ad-
vanced 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 inde-
pendent 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 com-
bined treatment whose most common side effect is myalgia i.e.
muscle pain, but taken as a single therapeutic agent also demon-
strates little efficacy in humans.
Neovastat (AE-941)
Neovastat is a standardized aqueous shark cartilage extract. Al-
though 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 Neovas-
tat prevents tumours form the formation of new capillaries in tu-
mours, thereby depriving them of oxygen and the nutrients they
need to grow, in fact both tumour growth and metastasis are de-
pendent 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 pa-
tients 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 analge-
sic drug. Essentially, Ziconotide, binding to presynaptic N-type
calcium channels, reversibly blocks their activity reducing the re-
lease of excitatory neurotransmitter [52]. Ziconotide received FDA
approval in December 2004 (Prialt1 is marketed by Elan Corpora-
tion, 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 Zicoti-
nide 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 struc-
turally simplified, synthetic analogue of the MNP Halichondrin B
was recently approved by the U.S. FDA (November 15, 2010) to

3554 Current Medicinal Chemistry, 20 11 Vol. 18, No. 23 Russo et al.
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 acade-
mia, had gone out of fashion for many in the pharmaceutical indus-
try" [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 ma-
rine 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 vin-
blastine (tight spirals) and Dolastatin 10 (aggregated rings and spi-
rals) [61]. It is most likely, as molecular modelling studies sug-
gested, 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 Eribu-
lin'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 pa-
tients, with several chemotherapic regimen, affected by locally
advanced, recurrent, or metastatic breast cancer (Table 1) [64-67].
Trabectedin ( YondelisTM, Formerly E T-743)
Since 1986, the Developmental Therapeutics Program of the
NCI acquired plants and marine organisms, through collection con-
tracts 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 com-
pound(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 anti-
cancer 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 alky-
lating 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 colla-
gen) and interaction with DNA repair mechanisms (e.g., the nucleo-
tide excision repair pathway) [71]. The transcription-coupled nu-
cleotide excision repair-(TC-NER)-dependent activity of Trabecte-
din 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 Halichondrin-
B.

From the Sea to Anticancer Therapy Current Medicinal Chemistry, 2011 Vol. 18, No. 23 3555
Table 1. Eribulin in Phase II-III Clinical Trials
Tumour Phase Schedules Evaluation Conclusion Ref.
Extensively pretreated patients with locally
recurrent or metastatic breast cancer.
Phase III
(762 patients randomized 2:1)
1.4 mg/m2i.v.
infusion on days 1 and 8 of
a 21-day cycle
Active
Recommended dose reductions
[64]
Extensively pretreated patients with locally
recurrent or metastatic breast cancer.
Phase III
(1102 patients randomized 1:1 for
Eribulin or capecitabine
1.4 mg/m2i.v.
infusion on days 1 and 8 of
a 21-day cycle
Ongoing [64]
Metastatic breast cancer previously treated
with an anthracycline and a taxane.
Phase II
(87 patients)
1.4 mg/m2i.v.
infusion on days 1 and 8 of
a 28-day cycle
Activity with manageable toler-
ability
[65]
Locally advanced or metastatic breast cancer
previously treated with an anthracycline, a
taxane, and capecitabine.
Phase II
(269 patients)
1.4 mg/m2i.v.
infusion on days 1 and 8 of
a 21-day cycle
Efficacious in a population of
extensively pretreated patients
[66]
Metastatic or recurrent squamous cell carci-
noma of the head and neck.
Phase II
(29 male, 11 female. Thirty-three
patients (83%) with metastatic dis-
ease)
1.4 mg/m2on
days 1 and 8 i.v. every 21-
day cycle.
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 ten-
dency to develop cancer [72]. The TC-NER machinery, like some
chemotherapeutic agents, is implicated in the repair of adducts de-
rived by alkylating agents. Trabectedin requires an efficient TC-
NER 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 DNA-
alkylating 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 Yondelis’s 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 ovar-
ian 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 Oc-
tober 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 sar-
coma) patients [76]. Development in patients with other malignan-
cies, such as breast and ovarian carcinoma, is currently ongoing
[77-79]. However, in July 2009 FDA rejected Yondelis (in combi-
nation) to treat ovarian cancer [80].
AplidinTM (Plitidepsin)
Plitidepsin (AplidinTM, PharmaMar USA Inc.) is a cyclic dep-
sipeptide isolated from the marine tunicate Aplidium albicans cur-
rently obtained by chemical synthesis as a didemnin second-
generation (Fig. 4).
Different studies elucidated the mechanism of action of Pliti-
depsin. Briefly it causes modulation of:
i. epidermal growth factor receptors
ii. non-receptor protein-tyrosine kinase SRC
iii. the serine/threonine kinases JNK, and p38 MAPK [81-83]
Moreover induces:
iv. cell cycle arrest at G1-S and inhibition of protein synthesis
[84-85]
v. inhibition of the signal transduction process targeting the
membrane-bound enzyme, palmitoyl thioesterase [86]
vi. inhibition of the vascular endothelial growth factor secre-
tion [87-88]

3556 Current Medicinal Chemistry, 20 11 Vol. 18, No. 23 Russo et al.
vii. inhibition of low molecular weight protein tyrosine phos-
phates [89]
viii. early induction of oxidative stress, activation of Rac1 small
GTPase, Rac1 translocation to cholesterol-rich membrane
domains and the later down-regulation of MAPK phospha-
tase 1 [90].
Phase I programs reported that Aplidin induced neuromuscular
toxicity, asthenia, skin toxicity, and diarrhoea, whereas no haemato-
logical 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
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 gastro-
pod mollusc in the family Aplysiidae [102]. In tasidotin the car-
boxyl-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 N-
desbenzylamino-cemadotin [103-104], inhibits mitosis without
significantly depolymerising or disorganizing the spindle microtu-
bules. Moreover, tasidotin inhibits weakly tubulin polymerization
into microtubules in vitro and in contrast with other microtubule-
targeted drugs it did not inhibit the growth rate. In contrast to stabi-
lizing plus ends, tasidotin robustly suppresses dynamic instability at
microtubule plus ends, whilst it weakly enhanced microtubule dy-
namic instability at minus ends. Interestingly, tasidotin C-
carboxylate is >10 times more potent than tasidotin. Thus, tasidotin
may be considered a rather weak prodrug, while tasidotin C-
carboxylate, may be the more active intracellular form of the com-
pound. The results imply that the principal mechanism of tasidotin
is suppressing spindle microtubule dynamics [105]. Briefly, tasi-
dotin 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-
Fig. (4). Aplidin.
Adapted from: [145] tunicate, [146] chemical structure Aplidin.
Table 2. Plitidepsin (Aplidin) in Phase II Trials
Tumour Schedules Conclusion Evaluation Ref.
Relapsed-refractory multiple myeloma 5 mg/m2 3 h i.v. infusion every 2 weeks +/-
20 mg/day on days 1 to 4 of oral dexametha-
sone every 2 weeks
Single-agent has limited but reproducible activity in relapsed/
refractory multiple myeloma patients
Activity observed after dexamethasone addition merits further
study
[95]
Advanced or metastatic urothelium transi-
tional cell carcinoma
5 mg/m2 3 h continuous i.v. infusion every 2
weeks
No objective tumour responses [96]
Unresectable advanced medullary thyroid
carcinoma
5 mg/m2 3 h i.v. infusion every 2 weeks Limited clinical activity [97]
Advanced malignant melanoma 5 mg/m2 3 h continuous i.v. infusion every 2
weeks
A minor degree of antitumor activity
Further evaluation in combination schedules may be warranted.
[98]
Unresectable advanced renal cell carcinoma 5 mg/m2 3 h continuous i.v. infusion every 2
weeks +/- L-carnitine
Some antitumor activity in selected patients [99]
Relapsed or progressed SCLC 3.2 mg/m2 1 h weekly i.v. infusion Absence of antitumor activity [100]
Locally advanced or metastatic NSCLC 5 mg/m2 3 h continuous i.v. infusion every 2
weeks +/- L-carnitine
Absence of antitumor activity [101]

From the Sea to Anticancer Therapy Current Medicinal Chemistry, 2011 Vol. 18, No. 23 3557
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 carci-
noma) warrants further disease-directed evaluations. Phase II stud-
ies, conducted in melanoma, NSCLC, and hormone-refractory pros-
tate 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 1,2-
aminoalcohol motif in an anti relationship (Fig. 6) [111]. Its pri-
mary 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, pharmacogenom-
ics, and efficacy of ES-285. In this phase I trial, ES-285 was admin-
istered as an i.v. infusion over 24 hours every 3 weeks. The maxi-
mum 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 reduc-
tions 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 en-
zyme 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 num-
ber 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 spec-
trometry 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 public-
ity, 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 ad-
vanced 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 con-
trolled human clinical trials for potential therapeutic agents, before
widespread handling, based only on media conjectures.
Fig. (5). Halichondrin-B and its derivatives.
Adapted from: [147] chemical structure Synthadotin, [148] chemical structure Dolastin-15, [149] mollusk.

3558 Current Medicinal Chemistry, 20 11 Vol. 18, No. 23 Russo et al.
Fig. (6). ES-285.
Adapted from: [150] Mollusk, [151] chemical structure ES-285.
Fig. (7). Lyprinol is a marine lipid extract from the New Zea-
land 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 Yon-
delis 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 phar-
macodynamic(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 thera-
pies. Although the mechanisms of action of these compounds are
different, the ultimate antitumour effects are due to induction of
apoptosis in cancer cells.
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 local-
ize 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 or-
ganism is killed in the process of obtaining the bioactive material,
and the majority of these eukaryotes cannot be cultured in labora-
tory, 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 inor-
ganic salts, (b) chemical diversity reflecting unlike and seldom
opposite pharmacological activities, (c) major presence of a non-
selective compound possibly covering the activity of minor selec-
tive 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 Ecteinascidin-
743 (Fig. 3) in 1996. Thus, Corey’s brief total synthesis allowed the

From the Sea to Anticancer Therapy Current Medicinal Chemistry, 2011 Vol. 18, No. 23 3559
1996. Thus, Corey’s 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 phar-
maceutical industries.
In conclusion, the importance of products from marine sources
might be attributed to the various structures, intricate carbon skele-
tons, 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 struc-
tures isolated from marine sources. Last but not least, environ-
mental 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, inverte-
brates 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 = 1- -arabinofuranosylcytosine
ALL = Acute Lymphoblastic Leukemia
AML = Acute myeloid leukemia
EMEA = European Agency for the Evaluation of Medicinal
Products
FADD = Fas-Associated protein with Death Domain
FDA = Food and Drug Administration
iv = Intravenously
LOX = Lipoxygenase
MNPs = Marine natural products
MTD = Maximum tolerated dose
NCI = National Cancer Institute
NSCLC = Non-small cell lung cancer
PKC! = Protein kinase C zeta
SCLC = Small Cell Lung Cancer
TC-NER = Transcription-coupled nucleotide excision repair
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Received: March 04, 2011 Revised: June 04, 2011 Accepted: June 05, 2011