In the movie The Medicine Man, Sean
Connery portrayed a physician who is sent into the deepest rain forest in search of new
tropical agents. His job was to comb through the endemic plant life in search of new
drugs, particularly anti-cancer agents that could be used in modern medicine. As the movie
unfolds Sean Connery has stumbled upon a plant extract from a bromeliad (a pineapple-like
plant) which cures tumors in his lab mice, only to find out greedy land developers are
slashing/burning the only area in the world where this plant is found. The bottom line is
when this great natural resource is gone, so to is the potential for many of these new
medicines.
The above paragraph sets the premise
for this column; many of the world reefs contain just such bioactive agents. Scientists
are scouring the sea in search of medicines that may work better than conventional drugs
with fewer side effects. As an example nature has provided many effective anticancer
agents in current use, such as the microbial derived drugs; bleomycin and doxorubicin; and
the plant-derived drugs, topotecan, and taxol. The search for novel anti-tumor agents from
natural sources continues through collaboration among scientists worldwide in the
investigation of coral reefs, and deep subsurface thermal vents for novel bioactive
compounds. The potential for drug discovery is further enhanced by recent advances in
procedures for microbial cultivation and the extraction of nucleic acids from
environmental samples, resulting in the identification of novel microbes that provide a
vast untapped reservoir of genetic and metabolic diversity.
For the remainder of my presentation I would like to
discuss novel applications and bioactive molecules found in reef dwelling marine organisms
(particularly, the ones we keep in our reef tanks) that have shown to possess beneficial
therapeutic qualities [1, 2a,b].
Proud sponsor of this column
Hard corals
Coral skeletons: Coral skeletons are
currently used in bone replacements in reconstructive surgeries. Coral structures have a
very regular and extensive interconnected pore system, and appear as biocompatible as
hydroxyapatite (the current standard for use in bone implants), in the formation of
potential bone replacements. In preliminary studies, coral skeletons have been implanted
into patients and examined for the shape of new bone, vascular patency, and induction of
bone. Upon examination all grafts had viable tissue, and heterotopic bone was formed. The
shape of the new bone was the same as that of the coral, and there was no significant
inflammatory reaction. Part of the coral in the composite was absorbed into the host. The
combination of coral skeletons impregnated with type 1 collagen is more effective in
forming autografts with designed shapes than current calcium hydroxyapatite sponges used
in maxillofacial reconstruction. Additionally, coral skeletons are less expensive than
currently available hydroxyapatite bone implants. [3, 4].
Galaxea: A protein
complex called S2 has been isolated from the mucus of G. fascicularis. The
S2 complex contains potent anti-topoisomerase activity, causing cytotoxicity to
multiple-drug resistant cancer cells. S2 inhibits DNA relaxation catalyzed by
topoisomerase I and II. Additionally S2 stabilizes the topoisomerase I-DNA cleavable
complex, thereby inhibiting the DNA replication machinery, leading to cell death. The
natural application of this complex in Galaxea is most likely to prevent bacterial
colonization on the mucus. S2 has potentials of being developed into a new anticancer
therapeutic [5].
Soft Corals
It is understood that soft corals produce
many toxic agents, these agents allow these sessile invertebrates to effectively compete
for space, but I bet you didn’t know how useful these toxic molecules can be
medically.
Gorgonians: Pseudopterogorgia
elisabethae. Biochemical screening of natural products derived from the sea whip have
been shown to have anti-tuberculosis activity. Scientists have identified two diterpine
alkaloids which when biologically screened against mycobacterium tuberculosis have shown
to posses potent growth inhibitors. These alkaloids are currently being synthesized and
will go into phase one clinical testing. [6].
Encrusting Gorgonians
Erythropodium caribaeorum,
Eleutherobin is a novel natural product
isolated from a marine encrusting gorgonian Erythropodium caribaeorum that is
extremely potent for inducing tubulin polymerization in vitro and is cytotoxic for cancer
cells with an IC50 similar to that of taxol. Taxol is currently one of the most effective
FDA approved anticancer agents available for treatment in ovarian, breast, and
non-small-cell lung carcinomas. Originally isolated from the bark of the Pacific yew, Taxus
brevifolia, it was the first natural product described that stabilized microtubules.
However, taxol has many pharmacokinetic limitations (such as multi-drug-resistance (MDR)
susceptibility, and lack of aqueous solubility) which make it a less than ideal drug.
Eleutherobin shares with taxol the ability to induce tubulin polymerization and is
cytotoxic by virtue of this mechanism. However the mechanisms of tublin polyermization by
eleutherobin are different than those of taxol induced polymerization. Additionally the
drug is water-soluble and appears to overcome multi-drug cross-resistance, making
eleutherobin one of the most promising new molecules with "taxol-like" activity
[7].
Palythoa.
Photo by Terry Siegel
Zoanthids (button polyps):
Zoanthids of the genus palythoa [See photo] posses an extremely potent toxin called
palytoxin (PTX). PTX is a toxin that blocks cellular Na+/K+-ATPases. Sub-lethal doses of
palytoxin have been injected repeatedly into mice bearing tumors, and PTX related effects
on reducing tumor tissues have been examined. This toxin has been chemically conjugated to
tumor-homing antibodies where the antibody provides a guided missile approach to
delivering this lethal warhead. Palytoxin has been reported as the causative agent in
mysterious fish death [8].
Interestingly, this toxin is also found in
various other marine organisms which live in close association with zoanthid colonies,
e.g. sponges (Porifera), soft corals (Alcyonaria), gorgonians (Gorgonaria), mussels, and
crustaceans. Additionally, predators of palythoa, e.g. polychaete worms (Hermodice
carunculata), a sea star (Acanthaster planci) and fish (Chaetodon
species) feeding on Palythoa colonies, accumulate high toxin concentrations in
their organs, where PTX is stored in its active form [9].
Xenia: a novel
diterpene called Xenicane has been isolated from the soft coral Xenia elongata.
Interestingly the terpenoid appears to be a fish specific poison, however it has shown
some effectiveness at inhibiting mitrochonridia respiration in cancer cells [10,11].
Pseudopterogorgia
(sea plume). Photo by Dave Playfair
Xenia.
Photo by jon (anative)
Nephthea: The soft
coral Nephthea was found to contain a bioactive compound called lemnabourside.
Lemnabourside is a 5alpha-reductase inhibitor which posses the ability to inhibit the
conversion of testosterone into the more potent dihydrotestosterone (DHT). The end result
is that lemnabourside selectively triggers cell death (apoptosis) in cancer cells.
Specifically, it is very active in prostate cancer cells, as they tend to be androgen
dependent [12].
Alga:
Alga: Two new drugs under
investigation by Nereus Pharma are derived from the marine green algae Halimeda (Halimeda
Opuntia). The drug Halimide [13, 14], a low molecular lectin-like molecule, appears to
have hemagglutinating activity, and has shown early promise in treatment of early stage
cancer, particularly breast cancers resistant to current chemotherapy. Additionally, in
the algae Halimeda Dictostia, a sulfated polysaccharide exhibits a potent antiviral
and anticoagulant activity has been identified. This compound known as HALOVIR A, a
sulfated galactan has shown antiviral activity against herpes simplex virus. The
inhibitory effect of the compound occurs during the adsorption period preventing viral
entry into a cell [15].
Proud sponsor of this column
Halimedia.
Photo by Dave ( cone9)
Scientists have found unique cyclic peptides known as
kahalalides in a mollusk which feeds exclusively on the green alga, Bryopsis. In
bioassays these kahalides (named A-F) have shown remarkable anti-tumor, antiviral,
anti-malarial, and OI (activity against AIDS opportunistic infections) activities [16].
The structure of these peptides is cyclic depsipeptides, ranging from a C(31) tripeptide
to a C(75) tridecapeptide and is responsible for their potent activities. Interestingly,
data show that both Bryopsis sp. and mollusk (Elysia rufescens) are
chemically protected against fish predators, as indicated by the deterrent properties of
their extracts at naturally occurring concentrations [17]. This is the first report of a
diet-derived depsipeptide used as a chemical defense in a sacoglossan.
Additonal reading.
1)-Discovery and development of
antineoplastic agents from natural sources. Cragg GM, Newman DJ. Cancer Invest;
17(2):153-63, 1999.
2)-a-Marine organisms as a source of new
anticancer agents.
Schwartsmann G, Brondani da Rocha A, Berlinck
R G, Jimeno J .Lancet Oncol Apr;2(4):221-5, 2001.
b-Marine natural products research: current
directions and future potential. Konig GM, Wright AD. Planta Med 1996 Jun;62(3):193-211
3)-Vascular osteomuscular autograft
prefabrication using coral, type I collagen and recombinant human bone morphogenetic
protein-2. Ma Q, Mao T, Liu B, Zhao J, Chen F, Wang H, Zhao M. Br J Oral Maxillofac Surg.,
Oct;38(5):561-4, 2000.
4)-The bioceramic orbital implant: a new
generation of porous implants. Jordan DR, Mawn LA, Brownstein S, McEachren TM, Gilberg SM,
Hill V, Grahovac SZ, Adenis JP. Ophthal Plast Reconstr Surg., Sep;16(5):347-55, 2000.
5)-A novel antitumour compound from the mucus
of a coral, Galaxea fascicularis, inhibits topoisomerase I and II. Fung FM, Ding JL.
Toxicon Jul;36(7):1053-8, 1998.
6)- Novel antimycobacterial benzoxazole
alkaloids, from the west Indian Sea whip Pseudopterogorgia elisabethae.Rodriguez AD,
Ramirez C, Rodriguez II, Gonzalez E. Org Lett., Aug 12;1(3):527-30,1999.
7)- Eleutherobin, a novel cytotoxic agent
that induces tubulin polymerization, is similar to paclitaxel (Taxol).Long BH, Carboni JM,
Wasserman AJ, Cornell LA, Casazza AM, Jensen PR, Lindel T, Fenical W, Fairchild CR. Cancer
Res., Mar 15;58(6):1111-5, 1998.
8)-Antibody -enzyme conjugates for cancer
therapy. Melton RG, Sherwood RF. J Natl Cancer Inst Feb 21;88(3-4):153-65, 1996.
9)-Distribution and sequestration of
palytoxin in coral reef animals. Gleibs S, Mebs D. Toxicon Nov;37(11):1521-7,1999.
10)- Bioactive diterpenoids from
Octocorallia, 2. Deoxyxeniolide B, a novel ichthyotoxic diterpenoid from the soft coral
Xenia elongata. Miyamoto T, Takenaka Y, Yamada K, Higuchi R. J Nat Prod Jun;58(6):924-8,1995.
11)-New xenicane diterpenes isolated from the
acetone extract of the soft coral Xenia florida.Iwagawa T, Nakamura K, Hirose T, Okamura
H, Nakatani M. J Nat Prod Apr;63(4):468-72, 2000.
12)- Growth inhibitory activity of
lemnabourside on human prostate cancer cells. Liu WK, Wong NL, Huang HM, Ho JK, Zhang WH,
Che CT. Life Sci, Jan 4;70(7):843-53, 2002.
13)- Dose-dependent selective cytotoxicity of
extracts from marine green alga, Cladophoropsis vaucheriaeformis, against mouse leukemia
L1210 cells. Harada H, Kamei Y., Biol Pharm Bull 1998 Apr;21(4):386-9.
14)- A chemical screening strategy for the
dereplication and prioritization of HIV-inhibitory aqueous natural products extracts.
Cardellina JH 2nd, Munro MH, Fuller RW, Manfredi KP, McKee TC, Tischler M, Bokesch HR,
Gustafson KR, Beutler JA, Boyd MR., J Nat Prod 1993 Jul;56(7):1123-9.
15)-Inhibitory effect of sulfated galactans
from marine alga on herpes simplex virus replication in vitro. Duarte ME, Noseda DG,
Noseda MD, Tulio S, Pujol CA, Damonte EB. Phytomedicine 2001 Jan;8(1):53-8.
16)-Kahalalides: Bioactive Peptides from a
Marine Mollusk Elysia rufescens and Its Algal Diet Bryopsis sp.Hamann MT, Otto CS, Scheuer
PJ, Dunbar DC., J Org Chem 1996 Sep 20;61(19):6594-6600.
17)-Chemical defenses of the sacoglossan
mollusk Elysia rufescens and its host Alga bryopsis sp. Becerro MA, Goetz G, Paul VJ,
Scheuer PJ., J Chem Ecol 2001 Nov;27(11):2287-99.
