20,000 Species Under the Sea: Diving to New Depths for Anti-Cancer Compounds

By Josh Southworth

Josh is an aspiring surgeon with a global surgery outlook. He is in his 2nd year studying graduate entry medicine at The University of Manchester, after completing his undergrad in Chemistry at The University of Oxford.

Cancer. The disease needs no introduction. In 2018 it affected the lives of roughly 17 million people, and 9.6 million of the cases were fatal (Data from Cancer Research UK). Despite the immense pressure cancer puts on societies around the globe, never has the armoury of techniques from chemotherapy to proton beam therapy been better equipped to fight back. Within the UK The Christie Hospital in Manchester is leading the charge against cancer, being the largest single site cancer hospital in Europe and sees around 44,000 patients per year. Of those who walk out the doors at the end of their care, I have no doubt all are grateful to the doctors, nurses and hundreds of support staff who keep the Christie’s operation going. I wonder though, how many are thankful to organisms like Ecteinascidia turbinata, a sea squirt resident to the Caribbean Sea for the help it played in treatment?

The marine world’s relationship with the oncology ward is nothing new. The Caribbean Sea sponge was the first to be investigated from 1950-1960 where breakthrough compounds were extracted from this innocuous organism. These compounds shone the light on the marine world and paved the way to Cytarabine which treats leukaemia and non-Hodgkin lymphoma. Despite this novel anti-cancer drugs from this source are extremely hard to come by. This is due to the rarity of finding a species containing chemicals which can be proven to have anti-cancer properties, as well as these chemicals forming in such miniscule amounts that extracting them and properly characterising them is a difficult process. Marine organisms need to produce fantastic and pharmaceutically diverse compounds as a means of chemical armour, protecting the user from extremes of temperature, salinity, pressure and high O2 concentrations, not to mention innate resistance to predators. Since the Caribbean Sea sponge scientists have been trawling (sometimes quite literally) the oceans looking for the next blockbuster anti-cancer compound like a needle in a haystack. The marine haystack isn’t exactly small either – oceans cover over 70% of the surface of Earth and within the murky depths it is estimates there are 500 million marine species lurking, a truly mind-bending number. However, this number is merely a warmup when compared to the number 3.7x1030, which isn’t in fact describing some astronomical event, but is the number of microorganisms that also call the oceans home. Based purely on these gargantuan numbers you can see the oceans are a huge reservoir for diverse life which is begging to be explored and it is surprising that less than 5% of the deep sea has been, and less than 0.01% of the deep-sea floor has been sampled in detail. Despite the scale of the oceans, scientists have found a plethora of organisms happily swimming around out which could form the next generation of anti-cancer weaponry.

Picture 1: Tectitethya crypta Caribbean sea sponge where spongothymidine and spongouridine were extracted, leading to the development of Cytarabine (picuture adapted from spongeguide.org)


The variety of organisms that have been found containing anti-cancer compounds is staggering. Topping the list for the currently most useful class of organisms are the marine sponges, which are responsible for contributing almost 30% of all natural products discovered to date. Think about that for a second. Medical science and its advancements are eating out of the hand of nature, cherry-picking roughly 325,000 natural products to be used in treating almost all illnesses and around 100,000 of these molecules come from a class of organism that aren’t even able to move sitting at the bottom of the sea. Out of the huge number of natural products isolated from sponges there are a number of potent anticancer drugs just like the aforementioned Cytarabine, one of the most promising drugs moving forward is Renieramycin found in Xestospongia sp. sponges which has shown encouraging preclinical results. It works by inducing tumour cell apoptosis via a tumour suppressing p53 protein dependant mechanism. When cells are exposed to Renieramycin p53 levels are elevated which down regulates levels of BCL-2 and MCL-1 anti-apoptotic proteins which stimulates apoptosis of tumour cells. Renieramycin has also been proven to increase the amount of anoikis, which is detachment -induced apoptosis which has been shown as one of the major ways to halt cancer metathesis.

Figure 1: Structure of Renieramycin












Another sessile organism crucial in the fight against cancer are soft corals where over 30 have been collected and studied. So far complex cembranoids compounds have mostly been extracted showing high in vivo cytotoxicity, proving effective against gastric epithelial, breast and liver cancer cell lines. Of the compounds isolated from soft corals Halichondrin B isolated from Halichondriidae corals is one of the most important in the fight against cancer due to its role in the discovery of the Eribulin which is an efficacious chemotherapy agent against stubborn breast cancers. Erbulin works by stoping cancerous cells from splitting mitotically, eventually this mitoticblockade results in apoptosis of said tumour cell.

Figure 2: Structure of Eribulin












Moving up from sponges and corals there is life in the ocean that ticks both boxes of being able to move and producing mind blowing natural products. A huge section of life in the oceans is contained within the algae family, which is cleaved into two smaller groups called macroalgae and microalgae. Macroalgae is the posh name of the incredibly popular seaweed which has been used in food, medicine and culture for millennia and known to contain scores of natural products. They are rich with important bioactive elements including carotenoids (the pigments that give plants some colour), fibre, essential fatty acids and numerous vital vitamins and minerals. More cancer orientated these organisms are a great source of molecules called polyphenols which are well known to science for their antioxidant and anti-cancer activity and have already proven effective at fighting tumours. These molecules are extremely common in marine plants like seaweeds and mangroves, which produce anti-cancer products very differently from terrestrial sources which alter telophase and thus reduce mitosis of cancerous cells. Of particular current interest are brown algae, currently being explored by scientists for their production of phloroglucinol, a molecule with potential as part of next generation of anti-cancer medication.

Microalgae are cyanobacteria which are the smaller relatives of seaweed. They are often referred to as blue-green algae and like seaweed have potent anti-cancer properties; in a recent study of 41 strains of cyanobacteria roughly half of them showed the ability to kill cancer cells. Just like on terra firma the seas are teaming with bacteria, and it isn’t just the cyanobacteria holding the limelight. Marine bacteria have produced a diverse list of bioactive substances and are well known for their production of anti-cancer quinone compounds, the compounds that make tonic water so … tonic-y. Further, two species called Lactobacilli and Noctiluca scintillans produce incredible compounds which are chemo preventive i.e. they actually protect your body from cancer before the tumour has had the chance to form. Seaweeds and algae go much further than just polyphenols and quinones though: they also produce polysaccharides (molecules like starch). These have not been examined as closely as polyphenols but that doesn’t mean they are any less efficacious. The poster-boy is a molecule called Fucoidan which works like most polysaccharides by triggering the innate immune system, culminating in the body fighting cancerous cells wherever the polysaccharide has raised the alarm.


As you’re probably imagining nature didn’t just stop here. Actinomycetes are an important subsection of bacteria which alone have yielded over 10,000 organic natural products. These peculiar bacteria’s land-dwelling relatives have been studied for a while, but it is only recently that the marine variants potency has been discovered, especially a compound isolated from an actinomycetes in the unassuming Mozambique Channel which has shown incredible toxicity towards lung and colon cancer cells in trials and could be part of the next line of cancer treatment.

Figure 3: Location of the Mozambique Channel

Wedged in between the kingdoms of plants and animals are the fungi, that strange section of biology that never seems to get the attention it deserved. It is a huge group of organisms with an estimated 1.5 to 3 million types globally and over the last 100 years many different compounds have been reported, including the hall of famer penicillin. These have displayed a wide variety of uses from antifungals to anti-cancer drugs. However, despite this we have extracted very little so far from the marine fungi subgroup. This recent realisation coupled to the oceans production line of novel natural products has meant this area is a hot topic of research with symbiotic lichens identified as a likely source of natural products.

Figure 4: Contributions of different marine flora to anticancer compounds (Taken from 2)


Adding to the classes of molecules already mentioned, peptide based compounds are universal across marine animals and are the current hot bed of anti-cancer drugs with over 2500 promising compounds being isolated in the last decade alone. These drugs are diverse in size and mode of action, meaning this group can cover a broad range of cancers from the prostate to pancreas. Currently it is the fungus Scopulariopsis brevicaulis that is drawing the most attention for its ability to make Scopularide A and B which apparently have the ability to fight skin, prostate, pancreas, colon and breast cancers, making it an incredibly versatile drug if found to be safe in the near future.


Strangely the least studied group is a group of chemicals that revolutionised the medical world. Morphine, nicotine and the less medicinally helpful cocaine all stem from this group. Any ideas? The alkaloids. The alkaloids have been studied for decades in land dwelling organisms and have already shown great anti-cancer activity with the breakthrough drug Taxol from the Western Yew tree, which has been fighting cancers since the mid 90s. However, the marine equivalents are extremely rare and relatively untouched until recently. Marine alkaloids work by inhibiting tumour growth and lucrative sources have been found in New Zealand and Fiji. They have been identified in mangroves, sponges, bacteria and ascidians and if they have the oomph of their terrestrial relatives, could provide the next wave of anticancer drugs to sweep the market.

Figure 5: Marine drugs in clinical trials, and the originating organism (Taken from 5)

Despite humanities awesome effort, cancer is not going anywhere soon, and although the incredible feats of staff at places like the Christie, the fight still claims precious lives. But I think it’s comforting knowing that nature is on our side. Yes, it is not making it easy and still hides her secrets like an oncologic holy grail, but it is satisfying to know that potentially thousands of miles away hundreds of metres below the waves, there are organisms blissfully unaware of their existence, that can produce unbelievable chemicals which may just help us beat cancer for good.

References

1. Towle, M. J. et al. Eribulin Induces Irreversible Mitotic Blockade : Implications of Cell-Based Pharmacodynamics for In vivo Efficacy under Intermittent Dosing Conditions. Am. Assoc. Cancer Res. 71, 496–506 (2011).

2. Boopathy, N. S. & Kathiresan, K. Anticancer Drugs from Marine Flora : An Overview. J. Oncol. 18 (2010). doi:10.1155/2010/214186

3. Halim, H. & Chunhacha, P. Anticancer and Antimetastatic Activities of Renieramycin M , a Marine Tetrahydroisoquinoline Alkaloid , in Human Non-small Cell Lung Cancer Cells. Anticancer Res. 202, 193–201 (2011).

4. Banerjee, P., Erehman, J., Wilhelm, T., Preissner, R. & Dunkel, M. Super Natural II –– a database of natural products. Nucleic Acid Res. 43, 935–939 (2015).

5. Khalifa, S. A. M. et al. Marine Natural Products : A Source of Novel Anticancer Drugs. Mar. Drugs 17, 31 (2019).

6. Farooq, A. et al. Natural products against cancer : Review on phytochemicals from marine sources in preventing cancer. Saudi Pharm. J. 27, 767–777 (2019).

7. Tun, J. O. et al. Synergistic Cytotoxicity of Renieramycin M and Doxorubicin in MCF-7 Breast Cancer Cells. Mar. Drugs 17, 1–26 (2019).

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