This document discusses marine anticancer drugs. It describes how marine organisms produce unique chemicals to withstand their harsh environments, making them a source of novel anticancer agents. Specific examples of anticancer compounds from marine bacteria, actinomycetes, fungi, microalgae, macroalgae, and soft corals are provided. Some successful marine-derived drugs on the market are also summarized, such as cytarabine, vidarabine, trabectedin, and eribulin mesylate. Cembranoids like sinularin and crassin acetate from soft corals are highlighted for their anticancer properties.
4. Marine Anticancer Drugs: Introduction:
Over 70% of the earth's surface is covered by oceans which contain 95% of the
earth's biosphere. Over time, they have evolved many different mechanisms to
survive the various harsh environments which include extreme temperatures,
salinity, pressure, different levels of aeration and radiation, overcoming effects of
mutation, and combating infection, fouling and overgrowth by other organisms.
Many different marine organisms have been explored for bioactive compounds.
Some vertebrate include fish, sharks and snakes. Examples of invertebrates are
sponges, coelenterates, tunicates, echinoderms, corals, algae, Mollusca and
bryozoans. Microorganisms include bacteria, fungi and cyanobacteria.
5.
6. Uniqueness of Marine Floral Drugs:
The marine floral resource will offer a great scope for discovery of new drugs. It
is increasingly recognized that ocean contains a huge number of natural products
and novel chemical entities with unique biological activities that may be useful
in finding the potential drugs with greater efficacy and specificity for the
treatment of human diseases.
The marine organisms produce novel chemicals to withstand extreme variations
in pressure, salinity, temperature, and so forth, prevailing in their environment,
and the chemicals produced are unique in diversity, structural, and functional
features.
7. Anticancer Agents from Marine Floras: 1. Bacteria
Marine microorganisms are a source of new genes, and exploitation of which is
likely to lead to the discovery of new drugs and targets. Secondary metabolites
produced by marine bacteria have yielded pharmaceutical products such as novel
anti-inflammatory agents (e.g., pseudopterosins, topsentins, scytonemin, and
manoalide), anticancer agents (e.g., bryostatins, discodermolide, eleutherobin,
and sarcodictyin), and antibiotics (e.g., marinone).
The contribution of probiotic bacteria, such as lactobacilli and bifidobacteria, is
mainly in the control of pathogenic microbes, through production of antibacterial
protein namely, bacteriocin and anticancer substances.
8. Anticancer Agents from Marine Floras: 2. Actinomycetes
For more than 50 years, the soil-derived actinomycetes of terrestrial origin have
provided a major pharmaceutical resource for the discovery of antibiotics and
related bioactive compounds. These microbes are found to be a potent sources of
anticancer agents that target proteasome function and their industrial potential is
validated by several pharmaceuticals.
Thiocoraline is a novel bioactive depsipeptide isolated from Micromonospora
marina, a marine microorganism located in the Mozambique Strait that inhibits
RNA synthesis.
9. Anticancer Agents from Marine Floras: 3. Marine Fungi
A rich profile of biologically active metabolites is described from filamentous
fungi of terrestrial origin, especially from just three genera: Penicillium,
Aspergillus, and Fusarium.
Marine-derived fungi are known to be a source of antioxidative natural products:
(i) Acremonin A from Acremonium sp. and (ii) Xanthone derivative from
Wardomyces anomalus. Antioxidants delay or prevent oxidative damage and thus
they may be useful as therapeutics or food additives.
10. Anticancer Agents from Marine Floras: 4. Micro Algae
Marine blue-green algae (Cyanobacteria) are considered to be one of the potential
organisms which can be the richest sources of known and novel bioactive
compounds including toxins with potential for pharmaceutical applications.
Scytonemin is a protein serine/threonine kinase inhibitor, isolated from the
cyanobacterium Stigonema sp. and this compound is a yellow-green ultraviolet
sunscreen pigment, known to be present in the extracellular sheaths of different
genera of aquatic and terrestrial blue-green algae. Scytonemin regulates mitotic
spindle formation as well as enzyme kinases involved in cell cycle control and the
compound also inhibits proliferation of human fibroblasts and endothelial cells.
11. Anticancer Agents from Marine Floras: 5. Macro Algae (Seaweed)
Seaweeds are important sources of protein, iodine, vitamins, and minerals and
hence, their metabolites have shown promising activities against cancer
incidences. The seaweeds also contain high amounts of polyphenols such as
catechin, epicatechin, epigallocatechin gallate, and gallic acid, as reported in
Halimeda sp. (Chlorophyceae). In the past three decades, many researchers have
worked on the antioxidant, antitumor, and immunomodulating activities of
seaweeds. Edible seaweed like Palmaria palmate is shown to be effective
antioxidant, capable of inhibiting cancer cell proliferation. The smear study
exhibits membrane blebbing, vacuole formation, and reduction in staining
intensity, which further ascertains the tumoricidal activity.
12. Marketed Marine Natural Products - Examples of Success Stories
Cytosar-U® and Vira-A® by Bedford Laboratories (Bedford, OH, USA) and King
Pharmaceuticals (Tenafly, NJ, USA),
cytarabine (FDA approved in 1969 for cancer)
vidarabine (FDA approved in 1976 as antiviral)
Cytarabine was chemically synthesized in 1959 and later produced by
fermentation of Streptomyces griseus. Curiously, the natural analogue of
cytarabine was later isolated from the gorgonian Eunicella cavolini but obviously
the extraction yield of 0.04% has turned this source economically impractible.
Cytarabine continues to be the election drug for the treatment of myeloid
leukaemia, non-Hodgkin‘s lymphoma and meningeal leukaemia. It may be used
alone or in combination with other anticancer agents.
13.
14. The first step to improve the bioavailability and stability of cytarabine was the
understanding of its mechanism of action and metabolism. Cytarabine has low
rates of passive diffusion across membranes and enters into the cells acting as
mimetic substrates (antimetabolic agents) for specialized nucleoside transporter
proteins. Although the mechanism of action is not completely understood, it
appears that cytarabine is converted intracellularly by deoxycytidine kinase, to
active cytarabine triphosphate. Activity occurs as the result of inhibition of DNA
polymerase via competition with deoxycytidine triphosphate, resulting in the
inhibition of DNA synthesis. A significant, incorporation of cytarabine into both
DNA and RNA has also been reported and may contribute to cytotoxic effects.
15. Marketed Marine Natural Products - Examples of Success Stories
Yondelis® by PharmaMar (Colmenar Viejo, Madrid, Spain)
Trabectedin (ET-743, Yondelis®) is a novel marine antineoplastic alkaloid with a
unique mechanism of action. Its action is not completely understood, but differs
from that of traditional alkylating agents as it appears to bind to the DNA minor
groove and interact with proteins of the DNA repair machinery. It is
commercialized by PharmaMar, and co-developed by Johnson & Johnson
Pharmaceutical Research and Development and is approved for use in Europe,
Russia and South Korea for the treatment of advanced soft tissue sarcoma. It is
also undergoing clinical trials for the treatment of breast, prostate, and pediatric
16. The active substance is a natural product, originally isolated from the Caribbean
sea squirt Ecteinascidia turbinata with a 0.0001% yield, the reason why the
structure of the active compound took 30 years to be elucidate.
17. Marketed Marine Natural Products - Examples of Success Stories
Halaven® by Eisai (Tokyo, Japan)
Eribulin mesylate (Halaven®) gained FDA‘s approval in 2010 and EMEA‘s in
2011, for metastatic breast cancer. Halichondrin B is a macrocyclic polyether
isolated from the first time in 1986 from the sponge Halichondria okadai and
found to be highly cytotoxic in murine leukemia cells. The total synthesis was
achieved by 1991 and subsequent studies identified the macrocyclic lactone C1–
C38 moiety as the pharmacophore. This discovery led the researchers from Eisai
Research Institute to synthesize a simplified macrocyclic ketone analogue
(Eribulin mesylate, former E7389) which kept the same level of activity.
18. Eribulin mesylate and halichondrin B fights cancer cells by inhibiting tubulin, a
protein component of the cytoskeleton which is needed to support the rapid
growth of cancer cells and is the target of several other cancer chemotherapies,
including taxol.
19. Cembranes:
Cembranoids are the 14-membered cyclic diterpenes obtained from a wide
variety of soft corals.
A few typical examples of naturally occurring cembranes are namely:
Sinularin, Crassin acetate, Cytarabine, Fludarabine & Aplysistatin.
20. 1. Sinularin:
B.S. : Sinularin & its dihydro congener are obtained from sinularia
flexibilis. (species of soft coral in the family Alcyaniidae)
It is commonly known as spaghetti finger leather coral. This species is
widespread throughout the western pacific & eastern Indian oceans. (found in
large colonies at depths between 1-15 meters).
Sinularin induces DNA damage, G2/M phase arrest,
and apoptosis in human hepatocellular carcinoma cells.
Uses: It possess anticancer activities.
21. 2. Crassin acetate:
B.S. : It is obtained from the Caribbean Gorgonian pseudoplexaura porosa.
It is the member of cembranoids which are cyclic diterpenes.
Uses: Crassin acetate was observed to be comparatively inert to the
mammalian system but on the contrary found to be extremely cytotoxic to
human leukemic cells in vitro & also to the mouse fibroblasts.