Anda di halaman 1dari 10

1536

Current Topics in Medicinal Chemistry, 2009, 9, 1536-1545

Anticancer Drugs Discovery and Development from Marine Organisms


Chiranjib Chakraborty*, Chi-Hsin Hsu, Zhi-Hong Wen and Chan-Shing Lin
Department of Marine Biotechnology and Resources, College of Marine Science and Division of Marine Biotechnology,
Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohisung
Abstract: The chemical and biological diversity of the different marine evolutionary group is endless and therefore, this
is an amazing resource for the discovery of new anticancer drugs. Comprising 34 of the 36 Phyla of life, marine
ecosystems are indeed our last genetic diversity and biotechnological boundary; terrestrial systems possess only 17 Phyla.
Sponges, coelenterates and microorganisms are the foremost resources of therapeutic compounds. Algae, echinoderms,
tunicates, mollusks, bryozoans are also the sources of anticancer drugs from marine resources. We highlight the past and
current status of marine anticancer pharmacology using different marine groups.

Keywords: Anticancer drugs discovery, marine families and evolution, marine biodiversity.
INTRODUCTION
The Ocean, the mother of origin of life, wrap over 70%
of the earths surface and contain highly ecological, chemical
and biological diversity starting from microorganisms to
vertebrates. This variety has been the resource of unique
chemical compounds, which hold great pharmaceutical
prospective. New trends in drug discovery from natural
sources emphasize on investigation of the marine ecosystem
to explore numerous complex and novel chemical entities.
These entities are the sources of new leads for treatment of
different diseases mainly different cancers. The marine
environment may contain over 80% of worlds plant and
animal species [1]. Recently, a lot of bioactive compounds
have been extracted from a range of marine animals. The
hunt for new metabolites from maritime organisms has
resulted in the isolation of more or less 10,000 metabolites
[2], many of which are endowed with pharmacodynamic
properties.
It was stated that the alive organisms have appeared in
the sea more than 3500 million years ago [3-4] and
evolutionary progress has equipped many marine organisms
with the appropriate mechanism to survive in a hostile milieu
in terms of extreme temperature, changes in salinity and
pressure as well as overcoming the consequence of mutation,
bacteria and viral pathogens [5]. Marine organisms have
developed exquisitely complex biological mechanisms
showing cross phylum activity with terrestrial organisms [6].
So, it is not a surprise that marine natural products have their
stranglehold in the vicinity of anti-cancer chemotherapy as
indicated by the list of compounds currently under clinical
examination. Quicker inspection of this record exposes that
marine invertebrates such as sponges, tunicates, bryozoans
and molluscs are the most interesting sources of pharmacologically active metabolites whereas for example seaweeds
that grow so abundantly or other marine algae appear to be
*Address correspondence to this author at the Department of Marine
Biotechnology and Resources, College of Marine Science and Division of
Marine Biotechnology, Asia-Pacific Ocean Research Center, National Sun
Yat-sen University, Kaohisung, Taiwan; E-mail: drchiranjib@yahoo.com;
shinlin@mail.nsysu.edu.tw
1568-0266/09 $55.00+.00

less promising in comparison. Marine organisms comprise


approximately a half of the total biodiversity, thus offering a
vast source to discover useful therapeutics (Fig. 1). According to Blunt et al. [7], sponges (37%), coelenterates (21%)
and microorganisms (18%) are the major sources of biomedical compounds followed by algae (9%), echinoderms
(6%), tunicates (6%), molluscs (2%) bryozoans (1%), etc.
In due course, the active ingredients from traditional
medicines were chemically purified, and in the 19th and 20th
centuries some of these drugs (e.g., morphine) were utilized
in single-ingredient formulations. As time passed, these
molecules became the foundation of the new discipline of
organic chemistry. Pharmaceutical companies also focus on
the purifying new drugs from these traditional ethnomedicines [8]. The enormous resources of the oceans lay
dormant until the mid to late 1960s when small groups of
organic chemists in the United States, Europe, and Japan
began to collect, extract, and chemically explore the
diversity of marine life and this was the journey when
marine medicine research was started. The purpose of this
article is to review the research literature published till date
in the field of marine anticancer pharmacology.
MARINE PLANT SUPERFAMILY AS A SOURCE OF
ANTICANCER DRUGS
Marine Bacteria Family
Marine microorganisms have received very little
attention for drug discovery from microorganisms. The
complexity in the search of metabolites from marine bacteria
is mainly due to the non-culturability. Over 99% of the
marine bacteria are non culturable in vitro [9]. The studies
made by the scientists at the Scripps Institution of Oceanography show that marine bacteria are capable of producing
unusual bioactive compounds that are not observed in
terrestrial sources [10,11]. Marine bacteria are emerging as
an exciting resource for the discovery of new classes of
therapeutics. The promising anticancer clinical candidates
salinosporamide A and bryostatin only hint at the incredible
wealth of drug leads hidden just beneath the ocean surface
[12]. Salinosporamide A (Fig. 2) is a potent proteasome
2009 Bentham Science Publishers Ltd.

Anticancer Drugs Discovery and Development from Marine Organisms

Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 16

1537

Fig. (1). Evolutionary tree of different marine family and phyla related to anticancer drug discovery and development. Correspondence
species are also pointed out from where anticancer compound are harvested.

inhibitor used as an anticancer agent that recently entered


phase I human clinical trials for the treatment of multiple
myeloma only three years after its discovery [13,14]. This
novel marine natural product is produced by the recently
described obligate marine bacterium Salinispora tropica
which is found in ocean sediment. Bryostatins (Fig. 2) are a
group of macrolide lactones first discovered in the late 1960s
in a species of bryozoan, Bugula neritina. It is believed to be
produced by symbiont bacteria to protect the bryozoan larva
from predation or infection, they have cytotoxic properties
and are under investigation as anti-cancer agents and as a
memory enhancement agent. Bryostatin in sub-nanomolar
concentrations has been shown to be a potent activator of
protein kinase C. Another polysaccharide B-1 was isolated
from a marine Pseudomonas species which shows cytotoxic
activity against human cancer cell lines [15]. So, there is a
tremendous potential of marine bacteria as a source of new
therapeutics within the areas of oncology.

an attractive and versatile group of bacteria of immense


biological importance. This group in general and marine
forms in particular is one of the richest sources of known and
novel bioactive compounds including toxins with wide
pharmaceutical applications is unquestionable. A unique
thiozoline-containing compound, curacin- A, has been
purified from the organic extract of marine filamentous
cyanobacterium Lyngbya majusculata [16]. This compound
shows some selectivity for colon, renal and breast cancerderived cell lines [17]. Four new epipolysulphanyldioxopiperazines were isolated from a culture of the fungus
Leptosphaeria spp. originating from the Japanese brown alga
Sargassum tortile [18]. Absolute stereochemistries were
determined by chemical analyses and transformations. Each
compound possessed significant cytotoxic activity against
the P388 cell-line, while one of the leptosins also exhibited
appreciable cytotoxicity against a disease-oriented panel of
39 human cancer cell-lines, and specifically inhibited two
protein kinases and topoisomerase-II [19].

Marine Cyanobacteria Family

Didemnin B (Fig. 3) [20], a cyclic antiproliferative depsipeptide isolated from the Caribbean tunicate Trididemnum
solidum [21], was the first marine natural product to enter
clinical trial as an antitumor agent [22]. Based on a close

Thought to be amongst the first organisms to colonize the


earth, Cyanobacteria are the photosynthetic ancestors of
chloroplasts in eukaryots such as plants and algae. These are

1538 Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 16

Chakraborty et al.

OH

O
O

O
O

Cl

O
NH

OH

O
OH

OH

Salinosporamide A

O
O

O
O

Bryostatin1

O
O

O
O

H2N

O
O

H OH

O O

O
O
O

OH

O
O

HO
O
HO

E7389
OH
Halichondrin B

Fig. (2). Chemical structures of Salinosporamide A, Bryostatin1, Halichondrin B and E7389 which are derive from marine organisms.

structural resemblance of the didemnins to known cyanobacterial metabolites, Rinehart speculated that these potent
cytotoxins likely derive from symbiotic cyanobacterium
living in association with the tunicate [23]. It showed
antitumor activity against a variety of models and has been
investigated in phase II clinical trials for the treatment of
breast, ovarian, cervical, myeloma, glioblastoma or astrocytoma, and lung cancers. Moreover, didemnin B displays
several in vitro biological activities, albeit with widely
varying potencies (>5 orders of magnitude) [24], suggesting
that the activities are mediated by different mechanisms.
Didemnin B inhibits the synthesis of RNA, DNA, and
proteins [25] and binds noncompetitively to palmitoyl
protein thioesterase [26]. Moreover, rapamycin inhibits the
didemnin-induced apoptosis of human HL60 cells,
suggesting activation of the FK-506 apoptotic pathway.
Didemnin B perhaps modulates the activity of FK-506
binding proteins as part of its immunomodulatory process
and thus leads to cell death via apoptosis [27]. However,
several bioactive compounds originating from marine
cyanobacteria have undergone preclinical and clinical studies
as anticancer drugs.

Seaweeds Family
Seaweeds are abundant in the intertidal zones and in clear
tropical waters. Marine algae have received comparatively
less attention for anticancer drugs. Marine seaweeds have a
remarkable and previously unknown capacity to produce
anti-tumor compounds. An anti-tumor compound was
isolated from Portieria hornemannii [28]. P. hornemannii is
found to be a novel source of cytotoxic penta halogenated
monoterpene, halomon, which exhibited one of the most
extreme examples of differential cytotoxicity in the
screening conducted by the National Cancer Institute (NCI),
USA. Halomon has been selected for preclinical drug
development since this compound shows toxicity to brain,
renal and colon tumor cell-lines and preliminary in vivo
evaluations have been encouraging [17]. Sargassum
carpophyllum from the South China Sea is the source of two
new bioactive sterols. These sterols induced morphological
abnormality in the plant pathogenic fungus Pyricularia
oryzae; also exhibited cytotoxic activity against several
cultured cancer cell lines [29]. In recent years, much
attention has been focused on polysaccharides isolated from

Anticancer Drugs Discovery and Development from Marine Organisms

H
N

N
O

1539

NH

Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 16

N
H

HN

HO

HN

H2N

H
N

NH

N
O

HN
O

NH

HN

N
O

H
H
N

HN

HO

Kahalalide F

Ulapualide A
O
N

HO

NH

NH

HO

O
HN

OH
O

N
O

OH

HO

N
H

ET743
Didemnin B

Fig. (3). Chemical structures of Kahalalide F, Ulapualide A, Didemnin B and ET743 which are derive from marine organisms.

seaweeds. Antitumor properties were noted from a sulfated


polysaccharide from the red seaweed Champia feldmannii
[30]. A natural product, named Viva-Natural, extracted from
a dietary seaweed Undaria pinnantifida has been found to be
therapeutically active against Lewis lung carcinoma (LLC).
Viva-Natural also demonstrated moderate prophylactic
activity against LLC in allogeneic mice. A combination
therapy of Viva-Natural and standard anticancer drugs was
additively or synergistically effective [31]. Eucheuma serra
agglutinin (ESA) is a lectin derived from a marine red alga
Eucheuma serra and binds specifically to mannose-rich sugar
chains. Reports have indicated that ESA have an effective
anti-tumor activity [32]. Another extract from a marine red
alga, Amphiroa zonata, shows selective cytotoxic activity to
human leukemic cells, but no cytotoxicity to normal human
dermal fibroblast (HDF) cells in vitro which may be a lead
compound of anticancer drugs [33]. Much anticancer drug
discovery is left to do with the marine algae and seaweeds
that should be started immediately.
MARINE INVERTEBRATE SUPERFAMILY AS A
SOURCE OF ANTICANCER DRUGS
Phyla: Sponge
About 10,000 sponges have been described in the world
and most of them live in marine waters ranging from tidal

zones to depths exceeding 8,800 metres. A range of bioactive metabolites has been found in about 11 sponge genera.
Three of these genera (Haliclona, Petrosia and Discodemia)
produce powerful anti-cancer, anti-inflammatory agents, but
their cultivation has not been studied [34]. Initial isolations
of the bromotyrosine metabolite psammaplin A from various
verongid sponges (e.g., Psammaplysilla sp.) were reported
simultaneously by several research groups in 1987.
Psammaplin A, a symmetrical bromotyrosine disulfide
possessing oxime moieties, was found to have potent cytotoxicity to P388 cells (IC50 of 0.3 Ag/mL), and to co-occur
with a dimeric metabolite, biprasin [35-37]. Additional
psammaplin compounds have since been isolated, including
various sulfated and salt derivatives (psammaplins B-L), and
the degraded cysteine dimer, prepsammaplin A. Several of
these were found to possess potent antibacterial activity. The
fact that the psammaplins have been isolated from a diversity
of sponge sources and that brominated aromatic amino
acid derivatives are common in marine bacteria suggests that
these metabolites may actually derive from biosynthetic
pathways of microorganisms living in association with
sponges. Recently, testing of known and new psammaplin
metabolites as DNA methyl transferase and histone
deacetylase inhibitors has been reported [38]. The discovery
of spongouridine, a potent tumor-inhibiting arabinosyl
nucleoside in Caribbean sponge Cryptotethia crypta, focused

1540 Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 16

attention on sponges as a source of biomedically important


metabolites. The identification of the pharmacophore led to
the synthesis of a new class of arabinosyl nucleoside analogues, one of which is arabinosyl cytosine, which is converted
into arabinosyl cytosine triphosphate and incorporated into
cellular DNA where it inhibits DNA polymerase, is already
in clinical use for the treatment of acute mylocytic leukemia
and non-Hodgkins lymphoma [39]. The compound
manoalide from a Pacific sponge has spawned more than 300
chemical analogs, with a significant number of these going
on to clinical trials as different drugs. An aminoacridine
alkaloid, dercitin, has been isolated from the deep-water
sponge, Dercitus spp. That possesses cytotoxic activities in
the low nanomolar concentration range and in animal
studies, prolongs the life of mice-bearing ascitic P388
tumours, and is also active against B16 melanoma cells and
small cell Lewis lung carcinoma [40,44]. Halichondrin-B, a
polyether macrolide from Japanese sponge Theonella spp.,
has generated much interest as a potential anticancer agent
[17,41]. The theopederins are structurally related to
mycalamide-A from marine sponge, Mycale spp. collected in
New Zealand [42] and onnamide-A from marine sponge,
Theonella spp. collected in Okinawa [43] , which show in
vitro cytotoxity and in vivo antitumour activity in many
leukemia and solid tumour model systems [49].
Isoquinolinequinone metabolite cribostatin from the Indian
Ocean sponge Cribrochalina spp. shows selective activity
against all nine human melanoma cells in National Critical
Technologies (NCT) panel [45]. Spongstatin, a macrocytic
lactone from the Indian Ocean collection of Spongia spp., is
the most potent substance known against a subset of highly
chemoresistant tumour types in the NCT tumour panel [46].
Hyrtios erecta collected from the Egyptian Red Sea has been
found to contain salmahyrtisol A and B and sesterstatins, all
of which have shown significant cytotoxicity in human
cancer cell-lines [47]. A peroxy steroid, from an Okinawan
species of the genus Axinyssa, has been found to inhibit the
growth of several human cancer cell-lines [48]. Three
oxygenated sterols have been obtained from a collection of
Polymastia tenax. The compounds have been found to have
significant cytotoxicity to a range of human and murine
cancer cell-lines [49]. The batzellines are pyrroloiminoquinones alkaloids obtained from the deep-water Caribbean
sponge Batzella sp (family Esperiopsidae, order Poecilosclerida). Batzellines exhibit selective cyto-toxicity towards
the pancreatic cancer cell lines AsPC-1, Panc-1, BxPC-3,
and MIA PaCa2 compared with the normal African green
monkey kidney epithelial cell line Vero. The batzellines
cause cytotoxicity by inducing cell cycle arrest that is
mediated by their ability to intercalate into DNA and/or
inhibit topoisomerase II activity. The cytotoxic abilities of
isobatzellines A and C against pancreatic cancer cell lines,
their low toxicity against normal cells, and their reported
ability to be synthesized makes them interesting compounds
with potential chemotherapeutic effects that may merit
further research [50]. Sipholenol A, a sipholane triterpene
isolated from the Red Sea sponge, Callyspongia siphonella,
potently reversed multidrug resistance (MDR) in cancer cells
that overexpressed P-glycoprotein (P-gp). Overall, the
present results indicate that sipholenol A efficiently inhibits
the function of P-gp through direct interactions, and
sipholane triterpenes are a new class of potential reversing

Chakraborty et al.

agents for treatment of MDR in P-gp-overexpressing tumors


[51]. Another chemical halichondrins were first isolated
from the Japanese sponge Halichondria okadai by Uemura et
al. and structures determined by X-ray crystallography [52].
Subsequently, halichondrin B and several natural analogues
were isolated from various unrelated sponges, including
Lissodendoryx sp., Phakellia carteri, and Axinella sp., and
thus strongly suggest that these skeletal types may be
constructed by an associated microorganism. A number of
studies subsequently examined their mechanism of cell
toxicity, and it was discovered that the halichondrins are
potent tubulin inhibitors, in this case noncompetitively
binding to the Vinca binding site and causing a characteristic
G2-M cell cycle arrest with concomitant disruption of the
mitotic spindle [53,54]. The role of marine sponge alkaloids
as anticancer agent should be investigated more and more.
Phyla: Cnidarians
The discovery of prostaglandin in corals in the late 1960s
contributed greatly to the rapid development in the field of
marine natural products [17]. The first chemical study of the
soft coral Lemnalia flava, collected off Mombasa, Kenya,
has yielded lemnaflavoside and three monoacetate
derivatives [55]. Clavubicyclone from Clavularia viridis
exhibited mild cytotoxicity towards MCF-7 and OVCAR-3
tumour cell-lines [48]. The Okinawan soft coral Clavularia
koellikeri resulted in the isolation of two new cembrane
diterpenoids (1 and 2) and one new dollabelane diterpenoid,
3. Their structures were determined on the basis of the
results of spectroscopic analysis. Compounds 1 and 3 were
examined for in vitro growth-inhibition effect toward tumor
cells [56]. Bioassaydirected fractionation of the soft coral
Cespitularia hypotentaculata yielded diterpene cespitularin
AD, a norditerpene cespitularin E and three further
diterpenes, cespitularin FH, with a novel skeleton [57]. Five
new suberosane sesquiterpenes, suberosenol A (1),
suberosenol B (2), suberosanone (3), suberosenol A acetate
(4), and suberosenol B acetate (5), along with the known
sesquiterpene subergorgic acid (6), have been isolated from
the gorgonian Isis hippuris. The structures of these
metabolites were established by spectroscopic and chemical
methods. Metabolites 1 and 35 were found to exhibit potent
cytotoxicity toward P-388, A549, and HT-29 cancer cell
lines [58].
Variable potency and selectivity was observed for the
eight compounds towards tumour cell-lines A-549, HT-29
and P388. Further [59] investigation of the stony coral
Montipora spp. from Korea yielded three diacetylene, one of
them were the most potent cytotoxin towards a range of
tumour cell-lines [60]. New examples of cadinene-skeleton
sesquiterpenes, xenitorins AF, have been isolated from
Xenia puerto-galerae [57]. The relative stereochemistries of
xenitorins A F are secured by nuclear overhauser enhancement spectroscopy nuclear magnetic resonance (NOESY
NMR) experiments. Xentorin A and E exhibited cytotoxicity
towards the A and P388 tumour cell-lines. Because of their
phenomenal biological activity in killing cancer cells and
great structural complexity, the halichondrins rapidly became
targets for chemical synthesis. The first total synthesis was
completed in 1990 [61]. The Kishi group focused on the
synthesis of structurally simplified halichondrin analogues

Anticancer Drugs Discovery and Development from Marine Organisms

which retained or had enhanced biological properties, and


this eventually led to the discovery of the clinical candidate
E7389. In addition to a substantial truncation of the left-hand
section of halichondrin B, E7389 (Fig. 2) also possess a
ketone which replaces a key destabilizing ester in the right
half of halichondrin B [62, 63]. Despite the roughly 35 steps
and <1.0% overall yield to E7389, it remains a tenable
clinical candidate because of its ultrapotency, and hence, a
relatively small mass of drug is sufficient to conduct clinical
trials, and ultimately, treat patients. Phase I clinical trials
with E7389 have been initiated using an accelerated dose
escalation schedule to evaluate maximum tolerated dose and
pharmacokinetics. Dose limiting toxicity was reached in one
patient at a single dose of 0.5 mg/m2, and a three-compartment model was described about the plasma pharmacokinetics. Plasma levels of E7389 in excess of those required
for cytotoxicity were observed in all patients for up to 72
hours, and patients with solid tumors are currently being
recruited for additional phase I trials.
Phyla: Bryozoans
Like cnidarians, bryozoans contain complex chemicals
that may be beneficial to humans. The bioactive compounds
are comparatively less in quantity from bryozoans. Most of
the extracted products are alkaloids [7]. The macrocyclic
lactone bryostatins, isolated from marine bryozoans, have
been found to be strong inhibitors of e.g., the P 388 murine
lymphocyte leukemia cell line and in vivo systems [64].
Bryostatin, the potent anti-cancer compound from Bugula
neritina [65,66], shows remarkable selectivity against human
leukemia, renal cancer, melanoma and non-small cell lung
cancer cell-lines. This compound modulates the signal
transduction enzyme protein kinase-C (PKC). The major
metabolite convolutamide-A from Anthia convoluta exhibits
in vitro cytotoxicity against L1210 murine leukemia cells
and KB human epidermoid carcinoma cells [67]. There are
two bryostatins isoform was identified other than Bryostatin
1 which are Bryostatin 5 and 8. Bryostatins 1, 5, and 8
induced equivalent inhibition of melanoma growth, but
bryostatins 5 and 8 induced less weight loss than bryostatin 1
[68]. Sudek et al. [69] identified the putative bryostatin
polyketide synthase gene cluster. However, many interesting
natural molecules from bryozoans with potential therapeutic
application yet to be discovered.
Molluscs Phyla
More than 2600 scientific studies over the last 20 years
testify to the important contribution of toxins extracted from
cone snails to medicine and cellular biology. These predatory animals produce an estimated approximately 100,000
distinct conotoxins, a vast majority yet to be discovered and
characterized [70]. To date, only 100 out of a potential
100,000 toxins have been extracted and analyzed [71]. Two
of these compounds, kahalalide F (Fig. 3) and ES285, have
been isolated from the Indopacific mollusc Elysia rufescens
and the North Atlantic mollusc Spisula polynyma,
respectively as potent anticancer agents [72]. Ulapualide-A,
(Fig. 3) a macrolide isolated from the nudibranch Hexabranchus sanguineus exhibits cytotoxic activity against L
1210 murine leukemia cells [73]. More efforts are needed in

Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 16

1541

the discovery of conopeptides, and their preclinical and


clinical development for anticancer drugs.
Phyla: Tunicates
Didemnin-B (Fig. 3) from the Caribbean tunicate
Trididemnum solidum was the first marine compound to
enter human cancer clinical trial as a purified natural product
[17] but was unsuccessful in further trials [74]. Nevertheless,
this class of cyclic peptides provides important structural
lead for a variety of antiviral, anticancer and immunosuppressant activities [75]. A study of the Thai ascidian
Ecteinascidia thurstoni, using a KCN-pretreatment isolation
procedure, identified the known two alkaloids ecteinascidins
and the two novel analogues ecteinascidins [76]. The identified ecteinascidins exhibited potent cytotoxicity towards
tumour cell-lines. ET-743 (Fig. 3) (Yondelis, trabectedin) is
a natural marine product with antitumour properties derived
from the tunicate Ecteinascidia turbinata. ET-743 binds to
the N2 position of guanine in the minor groove of DNA with
some degree of sequence specificity, altering the transcription regulation of induced genes. ET-743 is a new drug
with a novel mode of action, which has demonstrated activity in human tumours resistant to the available anticancer
drugs [77]. Further comparative studies are needed to define
the role of ET-743 alone or in combination in cancer
chemotherapy.
Phyla: Echinoderms
Physiologically active saponins have been studied
extensively from sea stars and sea cucumbers [78], but not so
useful as drugs because of their tendency to cause cell lysis
[17]. A new lanostane-type triterpene glycoside, impatienside A, was isolated from the sea cucumber Holothuria
impatiens, together with a structurally related, known
compound, bivittoside D. The two glycosides were found to
exhibit in vitro cytotoxicities similar to or better than those
of the potent anticancer drug etoposide (V-16) against seven
different human tumor cells [79]. Cationic porphyrins, which
interact with guanine quadruplex (G4) telomeric folds,
inhibit telomerase activity in human tumor cells. G4interactive agents exert their antiproliferative effects via
chromosomal destabilization and warrant their further
development as valuable anticancer tools [80]. However,
present new technologies may prove useful to screen for
echinoderms compounds of potential anticancer interest.
MARINE VERTEBRATE SUPERFAMILY
SOURCE OF ANTICANCER DRUGS

AS

Fish and Sea Snakes Family


Metabolites extracted from fish, sea snakes and aquatic
mammals are scanty. Various fish species are used to extract
fish oil, rich in omega-3 fatty acids, which are used in the
preparation of various kinds of drugs for the remedies of
human beings, such as arthritis and many others. Through
out the world about 500 species of fish are considered toxic.
Poison kills the poison, the famous proverb is the basis for
researchers in finding the biomedical metabolites from living
organisms. Lionfish spines carry lethal protein venom to the
unwary [81] can be tested as anticancer drug. Epidemiolo-

1542 Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 16

Chakraborty et al.

gical evidence strongly links fish oil, which is rich in


docosahexaenoic acid (DHA) and eicosapentaenoic acid
(EPA), with low incidences of several types of cancer. The
inhibitory effects of omega-3 polyunsaturated fatty acids on
cancer development and progression are supported by
studies with cultured cells and animal models [82]. Fish oilbased lipid emulsion (FO) rich in omega-3 fatty acids, which
were used in humans as a component of parenteral nutrition,
on the growth of the colon cancer cell line Caco-2 by Jordan
and Stein [83]. FO has a potent antiproliferative effect on
Caco-2 cells, at least in part, due to a decrease in the
progression of the cell cycle and the induction of apoptosis.
The combination of FO with 5-FU showed a successful
results in an additive growth inhibitory effect. For potential
anticancer drug candidates from antimicrobial peptides of
marine organisms, tilapia (Oreochromis mossambicus)
hepcidin TH2-3 was evaluated in several tumor cell lines by
Chen et al. [84]. These findings suggest a mechanism of
cytotoxic action of TH2-3 and indicate that TH2-3 may be a
promising chemotherapeutic agent against human fibrosarcoma cells.
The anti-tumor activity of the sea snake venom
(Hydrophis spiralis) was evaluated against Ehrlich`s Ascites
Carcinoma (EAC) in Swiss albino mice and HeLa and Hep2
tumor cell cultures [85]. The antitumor activity of the sea
snake venom (Lapemis curtus) was also evaluated against
Ehrlich's ascites carcinoma (EAC) in Swiss albino mice and
Table 1.

HeLa and Hep2 tumor cell cultures [86]. Sea snake venom
also benefit cancer patients with other malignancies including prostate, bladder, melanoma, brain, and Kaposi's
sarcoma. However further research is desirable for this.
CONCLUSION
Several therapeutics produced by 'Mother Nature' are still
in the front position of cancer chemotherapeutics. The
marine world has become a significant resource of anticancer
agents with new mechanisms of action. In recent years,
several reports [87-91] have been published about new
anticancer agents from marine world which are very promising. Although, thousands of new molecules are discovered
each year only small number of candidates is included in
clinical trials. The major difficulty underlying is the
sustainable supply of these compounds from natural sources.
Various strategies are developed like mariculture or aquaculture of source organisms, synthesis of synthetic analogues of
active compounds, fermentation of microorganisms producing the compound to solve the difficulty. An additional
strategy is the use of genetic engineering to transfer the
genes encoding the synthetic enzymes that produce the
desired compound to microorganisms which can be grown in
huge quantities. Different interdisciplinary sciences are also
required to develop the large quantity of product. However,
with the help of the subjects like pharmacology, molecular
biology, genomics, metagenomics, computational biology,

Several Marine Compound, their Source Group and Experimental Model for Anticancer Drug Development

Source Group

Compound

Experimental or Clinical Model or Clinical Trials

References

Bacteria

Cryptophycins

Murine in vivo xenograft models; Bovine brain tubulin

Panda et al. [92]; Menon et al., [93]

Cyanobacteria

Salinosporamide A

Rcently entered phase I human clinical trials for the treatment of


multiple myeloma

Chauhan et al. [14]; Feling et al. [13]

Didemnin B

Human phase II clinical trials for the treatment of breast, ovarian,


cervical, myeloma, glioblastoma or astrocytoma, and lung cancers

Johnson and Lawen [27]

colon, renal and breast cancer-derived cell lines

Gerwick et al [16];

Curacin- A

Crampton et al. [24];

Carte [17],
Lyngbyabellin A

Human nasopharyngeal and colon carcinoma cell line

Luesch et al.[95]

Discodermolide

Human and murine tumor cell lines

Martello et al. [96]

Fascaplysin

Human colon carcinoma and osteogenic sarcoma cell lines and


normal fibroblasts

Soni et al. [97]

Melophlins

Human c-H-rastransformed

Aoki et al. [98]

A and B

NIH3T3 cell line

Ecteinascidin-743

Human colon carcinoma cell line ; Transfected NIH 3T3


fibroblasts

Jin et al. [99]; Minuzzo et al. [100]

Ascididemin

Human and murine leukemia cell lines

Dassonneville et al. [101]

Bryozooa

Bryostatin-1

Human lymphoma cell line; Murine in vivo tumor model

Cartee et al. [102]; Koutcher et al.


[103]

Mollusc

ES-285 (Spisulosine)

prostate tumor PC-3 and LNCaP cell death

Snchez et al. [94]

Dolastatin 15

Human Phase clinical trials

Cunningham et al. [104]

Sponge

Tunicate

Anticancer Drugs Discovery and Development from Marine Organisms

combinatorial chemistry could be developed large quantity


of product and these subjects help us for the fundamental
research. This area of marine natural products is passing its
innovation phase and moving towards the second phase with
an understanding associations and progressions is driving the
research towards novel drugs from the sea. During next
decade, we will see momentous numbers of marine drugs
being used in the treatment of cancer. It will be an extension
of these studies to focus on numerous therapeutic areas of
growing human need. Finally, if we are to come back to
natural products as a source for new pharmaceutical compound, where else might we go?

Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 16


[9]

[10]
[11]
[12]
[13]

[14]

ACKNOWLEDGEMENTS
This work is particularly supported by "Aim for the Top
University Plan" of the National Sun Yat-sen University and
Ministry of Education, Taiwan.

[15]

ABBREVIATIONS
HL-60

Human promyelocytic leukemia cell line

FK-506

Fujimycin

ESA

Eucheuma serra agglutinin

AsPC-1

Human pancreatic tumor cell line

[17]

PANC-1

Human pancreatic carcinoma, epitheliallike cell line

[18]

MIA PaCa2

Human pancreatic cancer cell line

MCF-7

Human breast adenocarcinoma cell line

OVCAR-3

Human ovarian carcinoma cell line

HT29

Human colon adenocarcinoma grade II


cell line

[20]

A549

Human lung adenocarcinoma epithelial


cell line

[21]

ET-743

Ecteinascidin

HeLa cell

Cervical cancer cells taken from


Henrietta Lacks

[16]

[19]

[22]

REFERENCES
[1]
[2]
[3]
[4]
[5]

[6]

[7]
[8]

McCarthy, P.J.; Pomponi, S.A. A search for new pharmaceutical


drugs from marine organisms. Marine Biomed. Res. 2004, 22, 1-2.
Fuesetani, N. Drugs from the sea. In: Drugs from the sea; Chapt. 1,
Fuesetani, M. Eds., Basel: Karger, 2000, pp. 1-5.
Macdougall, J.D. A short history of planet Earth; John, W. Ed.,
New York, 1996, pp. 1-5.
Simmons, T. L.; Andrianasolo, E.; McPhail, K.; Flatt, P.; Gerwick,
W.H. Marine natural products as anticancer drugs. Mol. Cancer.
Ther. 2005, 4, 333-342.
Jimeno, J.; Faircloth, G.; Fernndez Sousa-Faro, J.M.; Scheuer, P.;
Rinehart, K. Review on new marine derived anticancer therapeutics. A journey from the sea to clinical trials. Mar. Drugs 2004, 2,
14-29.
Scotfield, V.I.; Schumpberger, J. M.; West, L.A.; Weissman, L.
Protocordate allorecognition is controlled by aq MHC-like gene.
Nature 1982, 295, 499-502.
Blunt, J.W.; Copp, B.R.; Munro, M.H.G.; Northcote, P.T.; Prinsep,
M.R. Marine natural products. Nat. Prod. Rep. 2004, 21, 1-49.
Gurib-Fakim, A. Medicinal plants: traditions of yesterday and drugs
of tomorrow. Mol. Aspects Med. 2006, 27, 1-93.

[23]
[24]

[25]
[26]
[27]

[28]
[29]

[30]

1543

Hugenholtz, P.; Pace, N.R. Identifying microbial diversity in


natural environment: a molecular phylogenetic approach. Trends
Biotechnol. 1996, 14, 190-197.
Fenical, W. Chemical studies of marine bacteria: developing a new
resource. Chem. Rev.1993, 93, 1673-1683.
Fenical, W.; Jensen, P.R. Marine Biotechnology; In: Attaway, D.;
Zaborsky, O. Eds., Plenum Press: New York, 1993, pp. 419-457.
Williams, P.G. Panning for chemical gold: marine bacteria as a
source of new therapeutics. Trends Biotechnol. 2009, 27, 45-52.
Feling, R.H.; Buchanan, G.O.; Mincer, T.J.; Kauffman, C.A.;
Jensen, P.R.; Fenical, W. Salinosporamide A: a highly cytotoxic
proteasome inhibitor from a novel microbial source, a marine
bacterium of the new genus salinospora. Angew. Chem. Int. Ed.
Engl. 2003, 42, 355-357.
Chauhan, D.; Catley, L.; Li, G.; Podar, K.; Hideshima, T.;
Velankar, M.; Mitsiades, C.; Mitsiades, N.; Yasui, H.; Letai, A.;
Ovaa, H.; Berkers, C.; Nicholson, B.; Chao, T.H.; Neuteboom, S.T.;
Richardson, P.; Palladino, M.A.; Anderson, K.C. A novel orally
active proteasome inhibitor induces apoptosis in multiple myeloma
cells with mechanisms distinct from Bortezomib. Cancer Cell 2005,
8, 407-419.
Matsuda, M.; Yamori, T.; Naitoh, M.; Okutani, K. Structural
revision of sulfated polysaccharide B-1 isolated from a marine
Pseudomonas species and its cytotoxic activity against human
cancer cell lines. Mar. Biotechnol. (NY) 2003, 5, 13-19.
Gerwick, W.H.; Proteau, P.J.; Nagh, D.G.; Hamel, E.; Blobhin, A.;
Slate, D.L. Structure of cruacin A, a novel antimitotic,
antiproliferative and brine shrimp toxic natural product from the
marine cyanobacterium Lyngbya majusula. J. Org. Chem. 1994, 59,
1243-1245.
Carte, B.K. Biomedical potential of marine natural products. Biosci.
1996, 46, 271-286.
Yamada, T.; Iwamoto, C.; Yamagaki, N.; Yamanouchi, T.;
Minoura, K.; Yamori, T.; Uehara, Y.; Andoh, T.; Umemura, K.;
Numata, A. Leptosins M-N1, cytotoxic metabolites from a
Leptosphaeria species separated from a marine alga. Structure
determination and biological activities. Tetrahedron 2002, 58, 479487.
Afiyatullov, S.S.; Kalinovsky, A.I.; Kuznetsova, T.A.; Isakov,
V.V.; Pivkin, M.V.; Dmitrenok, P.S.; Elyakov, G.B. New diterpene
glycosides of the fungus Acremonium striatisporum isolated from a
sea cucumber. J. Nat. Prod. 2002, 65, 641-644.
Developmental Therapeutics Compound Data Base. Bethesda
(MD): NIH/ National Cancer Institute (US) 2004. Available from
URL: http://dtp.nci.nih.gov/index.html
Rinehart, K.; Gloer, J.; Cook, J.; Carter, Jr.; Mizsak, S.; Scahill T.
Structures of the didemnins, antiviral and cytotoxic depsipeptides
from a Caribbean tunicate. J. Am. Chem. Soc. 1987, 103, 18571859.
Nuijen, B.; Bouma, M.; Manada, C.; Jimeno, J.M.; Schellens, J.H.;
Bult, A.; Beijnen, J.H.; Pharmaceutical development of anticancer
agents derived from marine sources. Anticancer Drugs 2000, 11,
793-811.
Sings, H.L.; Rinehart, K.L. Compounds produced from potential
tunicate-blue-green algal symbiosis. J. Ind. Microbiol. Biotechnol.
1996, 17, 385-396.
Crampton, S.; Adams, E.; Kuentzel, S.; Li, L.; Badiner, G.; Bhuyan,
B. Biochemical and cellular effects of didemnins A and B. Cancer
Res. 1984, 23, 1796-1801.
Vera, M.; Joullie, M. M. Natural products as probes of cell biology:
20 years of didemnin research. Med. Res. Rev. 2002, 22,102-145.
Crews, C.M.; Collins, J.L.; Lane, W.S.; Snapper, M.L.; Schreiber,
S.L. GTP dependent binding of the antiproliferative agent didemnin
to elongation factor 1 a. J. Biol. Chem. 1994, 269,15411-15414.
Johnson, K.; Lawen, A. Rapamycin inhibits didemnin B-induced
apoptosis in human HL-60 cells: evidence for the possible
involvement of FK506-binding protein 25. Immunol. Cell Biol.
1999, 77, 242-248.
Faulkner, D.J. Marine natural products. Nat. Prod. Rep. 2002, 19,
1-48.
Tang, H.F.; Yi, Y.H.; Yao, X.S.; Xu, Q.Z.; Zhang, S.Y.; Lin, H.W.
Bioactive steroids from the brown alga Sargassum carpophyllum. J.
Asian Nat. Prod. Res. 2002, 4, 95-105.
Lins, K.O.; Bezerra, D.P.; Alves, A.P.; Alencar, N.M.; Lima, M.W.;
Torres, V.M.; Farias, W.R.; Pessoa, C.; de Moraes, M.O.; CostaLotufo, L.V. Antitumor properties of a sulfated polysaccharide

1544 Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 16

[31]

[32]

[33]

[34]
[35]
[36]
[37]

[38]

[39]
[40]

[41]
[42]

[43]

[44]
[45]

[46]

[47]

[48]

[49]
[50]

[51]

from the red seaweed Champia feldmannii (Diaz-Pifferer). J. Appl.


Toxicol. 2009, 29, 20-26.
Furusawa, E.; Furusawa, S. Anticancer activity of a natural product,
viva-natural, extracted from Undaria pinnantifida on intraperitoneally implanted Lewis lung carcinoma. Oncology 1985, 42, 364369.
Fukuda, Y.; Sugahara, T.; Ueno, M.; Fukuta, Y.; Ochi, Y.;
Akiyama, K.; Miyazaki, T.; Masuda, S.; Kawakubo, A.; Kato, K.
The anti-tumor effect of Euchema serra agglutinin on colon cancer
cells in vitro and in vivo. Anticancer Drugs 2006, 17, 943-947.
Harada, H.; Yamashita, U.; Kurihara, H.; Fukushi, E.; Kawabata, J.;
Kamei, Y. Antitumor activity of palmitic acid found as a selective
cytotoxic substance in a marine red alga. Anticancer Res. 2002, 22,
2587-2590.
Blunt, J.W.; Copp, B.R.; Munro, M.H.G.; Northcote, P.T.; Prinsep,
M.R. Marine natural products. Nat. Prod. Rep. 2004, 21, 1-49.
Arabshahi, L.; Schmitz, F.J. Brominated tyrosine metabolites from
an unidentified sponge. J. Org. Chem. 1987, 52, 3584-3586.
Quinoa,` E.; Crews, P. Phenolic constituents of psammaplysilla.
Tetrahedron Lett.1987, 28, 3229-3232.
Rodriguez, A.D.; Akee, R.; Scheuer, P. Two bromotyrosinecysteine derived metabolites from a sponge. Tetrahedron Lett.
1987, 28, 4989-4992.
Pia, I. C.; Gautschi, J.T.; Wang, G.Y.; Sanders, M.L.; Schmitz,
F.J; France, D.; Cornell-Kennon, S.; Sambucetti, L.C.;
Remiszewski, S.W.; Perez, L.B.; Bair, K.W.; Crews, P l.
Psammaplins from the sponge Pseudoceratina purpurea: inhibition
of both histone deacetylase and DNA methyltransferase. J. Org.
Chem. 2003, 68, 3866-3873.
Ireland, C.; Copp, B.; Foster, M.; McDonald, L.; Radisky, D.;
Swersey, J. In: Marine Biology. Attaway, D.; Zeborsky, O.; Eds.,
Plenum Press: New York, 1993, pp. 1-43.
Burres, N.S.; Clement, J.J. Antitumor activity and mechanism of
action of the novel marine natural products mycalamide-A and -B
and Onnamide. Cancer Res. 1989, 49, 2935-2940.
Fuestani, N.; Sugawara, T.; Matsunago, S. Potent antitumor
metabolites from a marine sponge. J. Org. Chem. 1992, 57, 38283832.
Perry, N.G.; Blunt, J.W.; Munro, H.H.G. Mycalamide, A. Antiviral
compound from a New Zealand sponge of the genus Mycale. J. Am.
Chem. Soc. 1988, 110, 4850-4851.
Sakemi, S.; Ichiba, T.; Kohmoto, S.; Saucy, G. Isolation and
structure elucidation of onnamide A, a new bioactive metabolite of
a marine sponge. Theonella sp. J. Am. Chem. Soc. 1988; 110, 48514853.
Burres, N.S.; Sazech, S.; Gunavardana, G.P.; Clement, J.J.
Antitumor activity and nucleic acid binding properties of dercitin.
Cancer Res. 1989, 49, 5267-5274.
Pettit, G. R.; Collins, J.C.; Herald, D.L.; Tackett, L.P. Isolation and
structure of cribostatins1 and 2 from blue marine sponge,
Cribrochalina sp. Can. J. Chem. 1992, 70, 1170-1175.
Petitt, G.R.; Cichacz, Z.A.; Gao, F.; Herald, C.L.; Boyd, M.R.
Isolation and structure of the remarkable human cancer cell growth
inhibitors spongistatins 2 and 3 from an Eastern India Ocean
Spongia sp. J. Chem. Soc. (Lond Chem Commun) 1993, 1, 11661168.
Yousaf, M.; Sayed, K.A.; Rao, K.V.; Lim C.W.; Hu J.-F.; Kelly
M.; Franzblau S.G.; Zhang F.; Peraud, O.; Hill, R.T.; Hamann,
M.T. 12,34-Oxamanzamines, novel biocatalytic and natural
products from manzamine producing Indo-Pacific sponges.
Tetrahedron 2002, 58, 7397-7402.
Iwashima, M.; Terada, I.; Okamoto, K.; Iguchi, K. Tricycloclavulone and clavubicyclone, novel prostanoid-related marine
oxylipins, isolated from the Okinawan soft coral Clavularia viridis.
J. Org. Chem. 2002, 67, 2977-2981.
Santaf, G.; Paz, V.; Rodrguez, J.; Jimnez, C. Novel cytotoxic
oxygenated C29 sterols from the Colombian marine sponge
Polymastia tenax. J. Nat. Prod. 2002, 65, 1161-1164.
Guzmn, E. A.; Johnson, J.D.; Carrier, M.K.; Meyer, C.I.; Pitts,
T.P.; Gunasekera, S.P.; Wright, A.E. Selective cytotoxic activity of
the marine-derived batzelline compounds against pancreatic cancer
cell lines. Anticancer Drugs 2009, 20, 149-155.
Shi, Z.; Jain, S.; Kim, I.W.; Peng, X.X.; Abraham, I.; Youssef,
D.T.; Fu, L.W.; El Sayed, K.; Ambudkar, S.V.; Chen, Z.S.
Sipholenol A, a marine-derived sipholane triterpene, potently

Chakraborty et al.

[52]

[53]

[54]

[55]
[56]

[57]

[58]
[59]

[60]
[61]

[62]

[63]

[64]
[65]
[66]

[67]
[68]

[69]

[70]
[71]

reverses P-glycoprotein (ABCB1)-mediated multidrug resistance in


cancer cells. Cancer Sci. 2007, 98, 1373-1380.
Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama C, Tanaka J,
Okumura Y, Hirata Y. Norhalichondrin A: an antitumor polyether
macrolide from a marine sponge. J. Am. Chem. Soc. 1985, 107,
4796-4798.
Bai, R.L.; Paull, K.D.; Herald, C.L.; Malspeis, L.; Pettit, G.R.;
Hamel, E. Halichondrin B and homohalichondrin B, marine natural
products binding in the Vinca domain of tubulin. Discovery of
tubulin-based mechanism of action by analysis of differential
cytotoxicity data. J. Biol. Chem. 1991, 266, 15882-15889.
Dabydeen, D.; Florence, G.; Paterson, I.; Hamel, E. A Quantitative
evaluation of the effects of inhibitors of tubulin assembly on
polymerization induced by discodermolide, epothilone B, and
paclitaxel. Cancer Chemother. Pharmacol. 2004, 53, 397-403.
Rudi, A.; Levi, S.; Benayahu, Y.; Kashman, Y. Lemnaflavoside, a
new diterpene glycoside from the soft coral Lemnalia flava. J. Nat.
Prod. 2002, 65, 1672-1674.
Iwashima, M.; Terada, I.; Iguchi, K.; Yamori, T. New biologically
active marine sesquiterpenoid and steroid from the Okinawan
sponge of the genus Axinyssa. Chem. Pharm. Bull. 2002, 50, 12861289.
Duh, C.Y.; Chien, S.C.; Song, P.Y.; Wang,S.K.; El Gamal, A. A.;
Dai, C. F. New cadinene sesquiterpenoids from the Formosan soft
coral Xenia puerto-galerae. J. Nat. Prod. 2002, 65, 1853-1856.
Sheu, J.H.; Hung, K.C.; Wang, G.H.; Duh, C.Y. New Cytotoxic
Sesquiterpenes from the Gorgonian Isis hippuris. J. Nat. Prod.
2000, 63, 1603-1607.
He, X.X.; Su, J.Y.; Zeng, L.M.; Yang, X. P.; Liang, Y. J. Studies on
the secondary metabolite of the soft coral Lobophytum sp. Huaxue
Xuebao (ACTA Chim Sinica). 2002, 60, 334-337.
Alam, N.; Hong, J.; Lee, C.O.; Choi, J. S.; Im, K. S.; Jung, J. H.
Additional cytotoxic diacetylenes from the stony coral Montipora
sp. Chem. Pharm. Bull. 2002, 50, 661-662.
Cooper, A.; Salomon, R. Total synthesis of halichondrins:
enantioselective construction of a homochiral pentacyclic C1-C15
intermediate from D-ribose. Tetrahedron Lett. 1990, 31, 3813-3816.
Towle, M. J.; Salvato, K.A.; Budrow, J.; Wels, B. F.;
Kuznetsov, G.; Aalfs, K. K.; Welsh, S.; Wanjun, Z.; Seletsky, B.M.;
Palme, M.H.; Habgood, G.J. ; Singer ,L. A.; Dipietro, L. V. ; Yuan,
W.; Chen, J.J.; Quincy, D. A.; Davis, A.; Yoshimatsu, K.; Kishi, Y.;
Yu, M.J.; Littlefield, B. A. In vitro and in vivo anticancer activities
of synthetic macrocyclic ketone analogues of halichondrin B.
Cancer Res. 2001, 61, 1013-21.
Wang, Y.; Habgood, G.; Christ, W.; Littlefield, B.Y.; Melvin, J.
Structureactivity relationships of Halichondrin B analogues: modifications at C.30- C.38. Bioorg. Med. Chem. Lett. 2000, 10, 1029-32.
Mohr, H.; Pettit, G.R.; Plessing-Menze, A. Co-induction of lymphokine synthesis by the antineoplastic bryostatins. Immunobiology
1987, 175, 1-30.
Lilies, G. Gambling on marine biotechnology. Bioscience 1996, 46,
250-253.
Pettit, G.R. In: Progress in the Chemistry of Organic Natural
Products; Herz, W.; Kinby, G.W.; Steglich, W.; Tamm, C. Eds.:
Springer Verlag: Berlin, 1991, 57, 153-195.
Zhang, H.; Shigemori, H.; Ichibashi, M. Convolutamides A-F,
novel -lactam alkaloids from the marine bryozoan Amathia
convoluta. Tetrahedron 1994, 50, 10201-10206.
Kraft, A.S.; Woodley, S.; Pettit, G.R.; Gao, F.; Coll, J.C.; Wagner,
F. Comparison of the antitumor activity of bryostatins 1, 5, and 8.
Cancer Chemother. Pharmacol. 1996, 37, 271-278.
Sudek, S.; Lopanik, N.B.; Waggoner, L.E.; Hildebrand, M.;
Anderson, C.; Liu, H.; Patel, A.; Sherman, D.H.; Haygood, M.G.
Identification of the putative bryostatin polyketide synthase gene
cluster from "Candidatus Endobugula sertula", the uncultivated
microbial symbiont of the marine bryozoan Bugula neritina. J. Nat.
Prod. 2007, 70, 67-74.
Han, T. S.; Teichert, R.W.; Olivera, B.M.; Bulaj, G. Conus venoms
- a rich source of peptide-based therapeutics. Curr. Pharm. Des.
2008, 14, 2462-2479.
Pickrell, J. Wonder Drug snails face threats, Expert warn.
National Geographic News. 2003, 1-2. Available from URL:
http://news.nationalgeographic.com/news/2003/10/1016_031016_c
onesnails.html

Anticancer Drugs Discovery and Development from Marine Organisms


[72]

[73]
[74]
[75]

[76]
[77]

[78]

[79]

[80]

[81]
[82]

[83]

[84]

[85]

[86]

[87]

[88]
[89]

Faircloth, G.; Cuevas, C. Kahalalide F and ES285: potent


anticancer agents from marine molluscs. Prog. Mol. Subcell. Biol.
2006, 43, 363-379.
Rorsener, J.A.; Scheuer, P.J. Ulapualids A and B, extraordinary
antitumor macrolides from nudibranch egg masses. J. Am. Chem.
Soc. 1986, 108, 846-847.
Davidson, B.S. Ascidians: producers of amino acid derived
metabolites. Chem. Rev. 1993, 93,1771-1791.
Sakai, R.; Stroch, J.C.; Sullins, D.W.; Rinehart, K.L. Seven new
didemnins from the marine tunicate Trididemnin solidum. J. Am.
Chem. Soc. 1995, 117, 3734-3748.
Suwanborirux, K.; Charupant, K.; Amnuoypol, S.; Pummangura,
S.; Kubo, A.; Saito, N. Ecteinascidins 770 and 786 from the Thai
tunicate Ecteinascidia thurstoni. J. Nat. Prod. 2002, 65, 935-937.
D'Incalci, M.; Jimeno, J. Preclinical and clinical results with the
natural marine product ET-743. Expert. Opi. Investig. Drugs 2003,
12, 1843-53.
Dubois, M.A.; Higuchi, R.; Komori, T.; Sasaki, T. Structure of two
new oligoglycoside sulfates, pectinoside E and F, and biological
activities of 6 new pectinosides. Liegbigs Annalen der Chemis.
1988, 9, 845-850.
Sun, P.; Liu, B.S.; Yi, Y.H.; Li, L.; Gui, M.; Tang, H.F.; Zhang,
D.Z.; Zhang, S.L. A new cytotoxic lanostane-type triterpene
glycoside from the sea cucumber Holothuria impatiens. Chem.
Biodivers. 2007, 4, 450-457.
Izbicka, E.; Nishioka, D.; Marcell, V.; Raymond, E.; Davidson,
K.K.; Lawrence, R.A.; Wheelhouse, R.T.; Hurley, L.H.; Wu, R.S.;
Von Hoff, D. D. Telomere-interactive agents affect proliferation
rates and induce chromosomal destabilization in sea urchin
embryos. Anticancer Drug Des. 1999, 14, 355-365.
Saunders PR, Taylor PB. Venom of the lion fish, Pterois volitans.
Am. J. Physiol. 1959, 197, 437-440.
Siddiqui, R.A., Zerouga, M.; Wu, M.; Castillo, A.; Harvey, K.;
Zaloga, G.P.; Stillwell, W. Anticancer properties of propofoldocosahexaenoate and propofol-eicosapentaenoate on breast cancer
cells. Breast Cancer Res. 2005, 7, R645-654.
Jordan, A.; Stein, J. Effect of an omega-3 fatty acid containing lipid
emulsion alone and in combination with 5-fluorouracil (5-FU) on
growth of the colon cancer cell line Caco-2. Eur. J. Nutr. 2003, 42
324-31.
Chen, J.Y.; Lin, W.J.; Lin, T.L. A fish antimicrobial peptide, tilapia
hepcidin TH2-3, shows potent antitumor activity against human
fibrosarcoma cells. Peptides 2009, 30, 1636-1642.
Karthikeyan, R.; Karthigayan, S.; Balasubashini, M.S.;
Vijayalakshmi, S.; Somasundaram, S.T.; Balasubramanian, T.
Inhibition of cancer cell proliferation in vitro and tumor growth in
vivo by Hydrophis spiralis Sea Snake venom. Int. J. Cancer Res.
2007, 3, 186-190.
Karthikeyan, R.; Karthigayan, S.; Balasubashini, S.M.;
Somasundaram, S.T.; Balasubramanian, T. Inhibition of Hep2 and
HeLa cell proliferation in vitro and EAC tumor growth in vivo by
Lapemis curtus (Shaw 1802) venom. Toxicon 2008, 51, 157-161.
Kinghorn, A.D.; Chin, Y.W.; Swanson, S.M. Discovery of natural
product anticancer agents from biodiverse organisms. Curr. Opin.
Drug. Discov. Devel. 2009, 12, 189-196.
Napolitano, J.G.; Daranas, A.H.; Norte, M.; Fernndez, J. J. Marine
macrolides, a promising source of antitumor compounds.
Anticancer Agents Med. Chem. 2009, 9, 122-137.
Mayer, A.M.; Gustafson, K.R. Marine pharmacology in 2005-2006:
antitumor and cytotoxic compounds. Eur. J. Cancer 2008, 44,
2357-2387.

Received: August 4, 2009

Current Topics in Medicinal Chemistry, 2009, Vol. 9, No. 16


[90]

[91]
[92]
[93]

[94]

[95]

[96]

[97]

[98]

[99]
[100]

[101]

[102]

[103]

[104]

1545

Singh, R.; Sharma, M.; Joshi, P.; Rawat, D.S. Clinical status of anticancer agents derived from marine sources. Anticancer Agents Med.
Chem. 2008, 8, 603-617.
Adrian, T. Novel marine-derived anti-cancer agents. Curr. Pharm.
Des. 2007, 13, 3417-3436.
Panda, D.; Ananthnarayan, V.; Larson, G.; Shih, C.; Jordan, M.A.;
Wilson, L. Interaction of the antitumor compound cryptophycin-52
with tubulin. Biochemistry 2000, 39, 14121-14127.
Menon, K.; Alvarez, E.; Forler, P.; Phares, V.; Amsrud, T.;
Shih, C.; Al-Awar, R.; Teicher, B. A. Antitumor activity of
cryptophycins: effect of infusion time and combination studies.
Cancer Chemother. Pharmacol. 2000, 46, 1-149.
Snchez, A.M.; Malagarie-Cazenave, S.; Olea, N.; Vara, D.;
Cuevas, C.; Daz-Laviada, I. Spisulosine (ES-285) induces prostate
tumor PC-3 and LNCaP cell death by de novo synthesis of ceramide
and PKC activation. Eur. J. Pharmacol. 2008, 584, 237-245.
Luesch, H.; Yoshida, W.Y.; Moore, R.E.; Paul, V.J.; Mooberry,
S.L. Isolation, structure determination, and biological activity of
lyngbyabellin A from the marine cyanobacterium Lyngbya
majuscula. J. Nat. Prod. 2000, 63, 611-615.
Martello, L.A.; McDaid, H.M.; Regl, D.L.; Yang, C.P.; Meng, D.;
Pettus, T.R.; Kaufman, M.D.; Arimoto, H.; Danishefsky, S.J.;
Smith, A.B.; Horwitz, S. B. Taxol and discodermolide represent a
synergistic drug combination in human carcinoma cell lines. Clin.
Cancer Res. 2000, 6, 1978-1987.
Soni, R.; Muller, L.; Furet, P. Schoepfer, J.; Stephan, C.; ZumsteinMecker, S.; Fretz, H.; Chaudhuri, B. Inhibition of cyclin-dependent
kinase 4 (Cdk4) by fascaplysin, a marine natural product. Biochem.
Biophys. Res. Commun. 2000, 275, 877-884
Aoki, S.; Higuchi, K.; Ye, Y.; Satari, R.; Kobayashi, M. Melophlins
A and B, novel tetramic acids reversing the phenotype of rastransformed cells, from the marine sponge Melophlus
sarassinorum. Tetrahedron 2000, 56, 1833-1836.
Jin, S.; Gorfajn, B.; Faircloth, G.; Scotto, K.W. Ecteinascidin 743, a
transcriptiontargeted chemotherapeutic that inhibits MDR1
activation. Proc. Natl. Acad. Sci. USA 2000, 97, 6775-6779.
Minuzzo, M.; Marchini, S.; Broggini, M.; Faircloth, G.; D'Incalci,
M.; Mantovani, R. Interference of transcriptional activation by the
antineoplastic drug ecteinascidin-743. Proc. Natl. Acad. Sci. USA
2000, 97, 6780-6784.
Dassonneville, L.; Wattez, N.; Baldeyrou, B.; Mahieu, C.;
Lansiaux, A.; Banaigs, B.; Bonnard, I.; Bailly, C. Inhibition of
topoisomerase II by the marine alkaloid ascididemin and induction
of apoptosis in leukemia cells. Biochem. Pharmacol. 2000, 60, 527537.
Cartee, L.; Davis, C.; Lin, P.S.; Grant, S. Chronic exposure to
bryostatin-1 increases the radiosensitivity of U937 leukaemia cells
ectopically expressing Bcl-2 through a non-apoptotic mechanism.
Int. J. Radiat. Biol. 2000, 76, 1323-1333.
Koutcher, J.A.; Motwani, M.; Zakian, K.L.; Li. X.K.; Matei, C.
Dyke, J.P.; Ballon, D.; Yoo, H. H.; Schwartz, G.K. The in vivo
effect of bryostatin-1 on paclitaxel-induced tumor growth, mitotic
entry, and blood flow. Clin. Cancer Res. 2000, 6, 1498-1507.
Cunningham, C.; Appleman, L.J.; Visovatti, M.K.; Ryan, D.P.;
Regan, E.; Vukelja, S.; Bonate, P.L.; Ruvuna, F.; Fram, R.J.;
Jekunen, A.; Weitman, S.; Hammond, L. A.; Eder, J.P. Phase I and
pharmacokinetic study of the dolastatin-15 analogue Tasidotin
(ILX651) administered intravenously on days 1, 3, and 5 every 3
weeks in patients with advanced solid tumors. Clin. Cancer Res.
2005, 11, 7825-7833.

Revised: September 10, 2009

Accepted: September 12, 2009