Anticancer Drugs From Marine Sources
Metabolic products of marine organisms once considered to be deadly poisons to humans, tetrodotoxin and the conus peptides, are now leading to potential drugs for use in humans.
Thirty years ago, the main approach of the pharmaceutical industry toward drug discovery was based on combinatorial chemistry, a simple method to prepare a large number of compounds in a single process and identify useful compounds from among them. In contrast, a new trend on drug discovery in the last few years has been focused on natural products.
From the antibodies derived from animals to the metabolites obtained from plants, natural products are one of the main sources of compounds for drug discovery and have demonstrated considerable potential in the biomedical field. At least one-third of the current top twenty drugs in the market are obtained from a natural source, mainly plants.
The marine environment has produced a large number of very potent agents. These agents are able inhibit the growth of human cancer cells and exhibit other potential anticancer activities such as antimitotic activity (anti-tubulin and anti-actin effects), apoptosis or autophagy induction. Some are known to have the potential to inhibit migration, invasion or metastasis of cancer cells. Cyanobacteria targeting histone deacetylase, enzymes that are involved in transcription and almost all biological processes involving chromatins were also identified.
More than 20,000 novel chemicals have been found from marine sources so far, and that number is rising every year.
Cytarabine, Ziconotide, Trabectidin, Eribulin and Brentuximab vendotin are the marine-sourced drugs for cancer that are approved for human-use and are already on the market since many years. Furthermore, a large number of anti-cancer drugs that ameliorate the pain from cancers in humans or act as an adjuvant in immunological therapies are being studied.
Most of the marine-derived agents are single-celled organisms, ranging from eubacteria through to eukaryotes such as fungi and protists. Once known for production of harmful toxins, the marine blue-green algae are emerging as an important source of anticancer drugs.
Ziconotide is a chemical derived from the Conus magus toxin that acts as a painkiller with a potency 1000 times that of morphine.
It was approved by the U.S. Food and Drug Administration in December 2004 under the name Prialt and by the European Commission in February 2005
Ziconotide works by blocking calcium channels in pain-transmitting nerve cells, making them unable to transmit pain signals to the brain. It is administered through injection into the spinal fluid.
Eribulin is a completely synthetic compound of the marine natural product halichondrin-B. Halichondrin-B inhibits cell mitosis in the Halichondria genus of sponges.
Halichondria is a genus of massive, amorphous demosponges belonging to the family Halichondriidae.
This substance induces apoptosis of cancer cells following prolonged and irreversible mitotic inhibition and hence have become an important chemotherapy for cancers.
Brentuximab vedotin is an antibody-drug conjugate used to treat Hodgkin lymphoma (HL) and systemic ALCL. It selectively targets tumor cells expressing the CD30 antigen which is specifically present on cancer cells of HL and ALCL type.
It delivers a toxic microtubule-disrupting agent monomethyl auristatin E (MMAE) into CD30-expressing cells, It was approved by the US FDA in 2011. MMAE is a synthetic derivative of a compound called dolastatin 10 that is isolated from the marine shell-less mollusk Dorabella auricularia.
Brentuximab vedotin is marketed as Adcetris.
The nucleosides spongothymidine andspongouridine isolated from Tectitethya crypta led to the development of cytarabine.
Cytarabine is used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma.
Cytarabine was approved for human use in 1969. It is on the WHO's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is given by injection into a vein, under the skin, or into the cerebrospinal fluid.
Cytarabine (also known as cytosine arabinoside) combines a cytosine base with an arabinose sugar. Certain sponges in which cytarabine was originally found, use arabinoside sugars to form a different compound that is not a part of DNA.
Cytosine arabinoside is similar to human in an aspect that cytosine deoxyribose can be incorporated into human DNA, but different in a way that it kills the cell. It blocks with the synthesis of DNA. Its mode of action is due to its capability of rapidly converting into cytosine arabinoside triphosphate, which is responsible for damaging the DNA in the S phase (synthesis of DNA) of the cell cycle. For that reason cancer cells that are rapidly dividing are most affected.
Trabectidin is a drug isolated from Ecteinascidia turbinata, a species of sea squirt.
Trabectedin blocks DNA binding of the oncogenic transcription factor FUS-CHOP and reverses the transcription process in myxoid liposarcoma. By reversing the transcription created by this transcription factor, trabectedin causes differentiation and reverses the dividing capability of these cells.
Trabectedin is marketed under the brand name Yondelis. It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma.
Future directions and limitations
In the past two decades, a large screening of marine compounds has been conducted and several activities such as antiviral, antibacterial, antifungal, antiparasitic, antitumor and anti-inflammatory have been reported.
Marine compounds are also becoming an option to be developed into ingredients for the cosmetics. It is known that for thousands of years that the ointments, concoctions and cataplasms of algae and marine muds have been used for treating endless diseases especially in traditional Chinese and Japanese medicines.
The marine compounds could also become an option for the treatment of drug-resistant infections.
Nevertheless, some important things must be considered that can stand a barrier for research of marine-sourced compounds such as the low amounts in which these products are produced by the organisms (a large amount will be required for preclinical testing), the potential presence of toxins and inorganic salts derived from the organisms or environment, the wide diversity of chemical compounds produced by an organism, and the existence of nonspecic pharmacological targets.
- Veronica R.T., Encinar J.A., Lopez M.H., Sanchez A.P., Galiano V., Catalan E.B et al. An Updated Review on Marine Anticancer Compounds: The Use of Virtual Screening for the Discovery of Small-Molecule Cancer Drugs. Molecules 2017, 22, 1037.
- Leal, M.C.; Madeira, C.; Brandao, C.A.; Puga, J.; Calado, R. Bioprospecting of marine invertebrates for new natural products—A chemical and zoogeographical perspective. Molecules 2012, 17, 9842–9854.
- Mazard S., Penesyan A., Ostrowski M., Paulsen I.T., Egan S. Tiny microbes with a big impact: The role of cyanobacteria and their metabolites in shaping our future.Mar. Drugs. 2016;14:97 doi: 10.3390/md14050097.