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13.9.3 CYANOBACTERIA
Around half of the 41 cyanobacteria strains that were examined have the capacity to
kill cancer cells. Dolastatin 10 and curacin A, two antimicrotubule medicines produced
from cyanobacteria, have been tried and tested in human trials as cancer therapies and as
starting points for further synthetic analogs and derivatives. In vitro investigations showed
the pentacyclic chemicals Calothrixins A and B, both produced from the cyanobacterium
Calothrix
, at concentrations of 40 and 350 nM, respectively (Ojha et al., 2020).
Both these strains belong to the genus Nostoc and are found in the ocean. It has been
shown to have potent cytotoxic effects on the cell lines LOVO and KB, which stand
for human colorectal adenocarcinoma and human epidermoid carcinoma, respectively.
Human cancer research relies on both these cell lines. Excellent antiproliferative effect
could be shown via the use of the one-of-a-kind chemical scaffold known as argazole,
which was derived from Symploca sp. The Lyngbyaboulloni strain that had shown cytotoxicity against cancer served as the source for the discovery of the parent substance,
apratoxin A (Denny, 2021).
Tubulin is prevented from joining together by a family of anticancer chemicals called
cryptophycin, which are generated by cyanobacteria. A number of different taxa of
blue-green algae found both on land and in water have been shown to have scytonemin
in their extracellular sheaths. The progression of the mitotic spindle and the activity of
enzyme kinases, which are responsible for controlling the cell cycle, are both under the
control of this chemical. Further, it inhibits the growth of human endothelial and broblast
cells. Burkitt lymphoma cell lines were observed after the treatment with this medication
(IC50 = 9 and 200 nM). In nanomolar quantities, a class of chemicals known as apratoxin,
which is produced by cyanobacteria, block cancer cell lines (Kurhekar, 2020).
Apoptotic activity from multiple strains of cyanobacteria was able to kill acute myeloid
leukemia cells; however, healthy cells such as hepatocytes and cardiomyoblasts were safe
from its lethal effects. Recent studies have shown that cultivated benthic cyanobacteria
from temperate marine habitats constitute an underutilized, but potentially useful, source
for the discovery of new leukemia therapeutics. There is evidence that some marine cyanobacteria might serve as potential sources for the industrial production of vitamins with high
market value (B complex, E). It was found in a species of the cyanobacterium known as
stigonema that contains scytonemin which is responsible for regulating both the formation
of mitotic spindle and the activity of enzyme kinases, the fundamental regulators of the
cell cycle. In addition to this, it inhibits the expansion of human endothelium and broblast
cells. As a consequence of this, scytonemin may be an excellent protein kinase inhibitor
that also has qualities that are antiproliferative and anti-inammatory.
13.9.4 BACTERIA
Bryostatins, discodermolide, eleutherobin, and sarcodictyin are only a few examples of the
innovative anti-inflammatory, anticancer, and antibiotic medicinal compounds that have
been made from secondary metabolites generated by marine bacteria (e.g., marinone).
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By producing bacteriocin, an antibacterial protein, and other anticancer compounds, probiotic bacteria such as lactobacilli and bifidobacteria play a major role in the regulation of
pathogenic germs. According to reports, lactobacilli dietary supplements are reducing the
development of experimental colon cancer. Cellular responses are another mechanism by
which they regulate cell growth and death (Mestre et al., 2020) (Figure 13.4).
13.9.5 PROTEOBACTERIA
Actinobacteria and filamentous fungus have been the primary producers of Gram-positive
antibiotics, while Gram-negative bacteria have received substantially less attention in terms
of scientific study and antibiotic discovery. Biosynthetic gene clusters in Gram-negative
bacteria of the phylum Proteobacteria are likely to encode valuable substances, although
this fact was only recently found through the process of genome mining. The bacteria
belonging to the families V ibrionaceae, Enterobacteriaceae, and Pseudomonadaceae are all
classified as pathogens and are part of the phylum Proteobacteria. Despite the widespread
presence of Proteobacteria in marine settings, only a small percentage of the bioactive
compounds Bacteriocins, Lactic acid, Butyric acid, and Amino acid metabolites produced
by these bacteria have been discovered (Bech et al., 2020).
FIGURE 13.4 Marine microorganisms showing decomposition and consumption.
Image credit: https://earthobservatory.nasa.gov/features/Phytoplankton
⏎
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13.9.6 CYANOBACTERIA
Only the cyanophyta, the only bacterial phylum, obtain their energy through sunlight
rather than fermentation. Additionally, this group of photosynthetic prokaryotes is
unique in that it can generate oxygen even while it consumes carbon dioxide. Despite
the fact that certain cyanobacteria are notoriously difficult to cultivate, there has
been a recent uptick in interest in the study of these microorganisms in the context of
basic research. Filamentous and unicellular cyanobacteria have been collected over
time, identified using morphological and molecular criteria, and cultivated in axenic
cultures following standard procedures. With the use of screening procedures with
target species that were unrelated to those for whom the metabolites were manufactured, a great number of bioactive components that are produced by cyanobacteria
and algae have been identified. Some of these chemicals influence numerous cellular
biochemical processes (mostly those involved in the photosynthetic process) due to
their elevated biological activity and unique chemical structures. These chemicals may
be utilized as organic herbicides or as bio-control agents due to their potential function
in the regulation and succession of bacterial and algal populations. Both these uses
may be beneficial to the natural world. These are compounds that are unique to a small
number of taxonomic groupings and are not required for the core metabolic process
or the development of the organism. Additional important anticancer compounds
derived from marine cyanobacteria include dolastatin, cryptophycin, and curacin A, all
of which have undergone either preclinical or clinical testing as potential treatments
(Lang-Yona et al., 2022).
13.9.7 ACTINOMYCETES
For well over 50 years, soil-acquired actinomycetes have been a valuable pharmaceutical
resource in the search for antibiotics and other related bioactive chemicals. However,
scientists have only recently begun to investigate marine actinomycetes. The highly polar
trioxacarcin derivative gutingimycin was initially identified in sand. The Streptomyces
genus is the source of this derivative. Trioxacarcins D through F, as well as the more
well-known trioxacarcins A through C, are all produced by the same species of
Streptomyces. Actinomycetes found in marine environments that are members of the
family Micromonosporaceae are among the bacterial species that may manufacture
antibiotics, and there is reason to be optimistic about their potential. It has been established
that these bacteria are strong providers of anticancer treatments that target proteasomes,
and several medications have verified the economic potential of these microorganisms.
In the Mozambique Strait, the marine organism Micromonospora marina was found to
have a brand-new bioactive depsipeptide called thiocoraline. This depsipeptide inhibits
the creation of RNA. Moreover, the bioactive compound is selectively cytotoxic to cancer
cell lines derived from melanoma, lung, and colon cancer. It is noteworthy to notice that
the medicine inhibits cell growth within colon cancer cell lines with impaired p53 systems
more effectively than in other types of cancer cell lines. The anticancer agent thiocoraline
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exemplifies the use of artificial culture as a potential solution to problems associated with
the availability of drugs and serves as an example of a treatment that was developed from
marine microorganisms (Ruocco et al., 2022) (Figure 13.5).
FIGURE 13.5 Marine actinomycetes.
Source: Reprinted with permission from Kumar
⏎
et al. (2020). Copyright 2020. Springer Nature.
13.9.8 MARINE FUNGI
Yet, compared to their terrestrial cousins and other ecological groupings, marine fungus
has received the least amount of research. Research into marine facultative fungi has been
motivated by the discovery that these organisms synthesize chemicals that are not found in
their terrestrial counterparts. On the other hand, obligatory marine fungus is still mostly an
untapped resource. Research on the physiologically active metabolites produced by higher
fungi (Basidiomycota), endophytic fungi, marine filamentous fungi, and symbiotic lichens
has increased in recent years (Garlapati et al., 2021) (Figure 13.6).
13.9.9 SOFT CORALS
In tropical and subtropical seas, the soft coral genus Sarcophyton is extremely prevalent.
The biological activities of cephalosporins, such as ichthyotoxicity, cytotoxicity, antiinflammatory , and antagonistic activity, are af fected by these molecules. Also, crassumolide
C was first isolated from Lobophytumcrissum and was found to have a cytotoxic effect
−1
toward Ca9-22 cancer cells with an IC50 of 1.7 g mL
when compared to doxorubicin, an
appositive control (Mestre et al., 2020).
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FIGURE 13.6 Marine fungi.
⏎
13.9.10 MARINE SPONGES
These microbial communities were responsible for the discovery of almost 30% of all
natural products to this far. Based on these initial results from marine sponges, it seems
likely that we will not have to wait long before we can buy real drugs made from marine
ingredients. Antiviral activity of these compounds was discovered, leading to the development of the anticancer medication cytosine arabinoside (AraC) through the study of
synthetic analogs. Eribulin is a synthetic abbreviation of halichondrin B. Eribulin may
have therapeutic effects on breast cancer cells that have metastasized despite prior treatment (Garlapati et al., 2021).
13.10 ANTICANCER BIOACTIVE ANTIBIOTICS DERIVED FROM MARINE SOURCES
Polysaccharides, polyphenols, and alkaloids are some of the most effective and physiologically strong anticancer compounds that have been identified in marine organisms.
Polyphenols and polysaccharides make up the most frequent category of marine
compounds that may be used for their potential antioxidant and anticancer effects.
Mangrove plants are a source of essential nutrients such as amino acids, enzymes, bioflavonoids, trace elements, and fatty acids. Macroalgae experience rapid growth, which
results in the production of a significant amount of biomass (Karthikeyan et al., 2022).
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Macroalgae have the benefit of not requiring any land or water to grow, in addition to
having a higher rate of photosynthetic activity than the biomass found in terrestrial environments. Since they contain a significant amount of phycoerythrin, they have a distinctively red color. As a potential food reserve, red seaweed may be able to metabolize.
Floridean starch is a storage glucan found in red algae or rhodophyceae and is similar to
amylopectin and glycogen. Carbohydrates make up over half of the dry biomass of brown
algae, giving them high carbohydrate content. Brown algae has high nutritional value and
they are used in making the chemical alginate (Vuong, 2021).
13.10.1 POLYPHENOLS
Phytochemicals such as catechin, epicatechin, epigallocatechin gallate, and gallic acid abound
in seaweeds, sea grass, and mangroves. The anticancer, antiviral, and anti-inflammatory capa bilities of polyphenolic compounds, as well as their ability to prevent platelets from sticking
together, are just the tip of the iceberg of the health-promoting bioactivities that have been
demonstrated for them. Several studies have found that a diet rich in natural antioxidants is
associated with a reduced mortality risk from cardiovascular disease and cancer, as well as an
enhanced lifespan. They are also powerful antioxidants and natural metal chelators, so they
can be utilized to protect against a variety of organ dysfunctions brought on by metal ions.
The marine red algae Osmundea pinnatifida has been shown to have antioxidant, antibacterial, antifungal, and antileishmanial properties (Figure 13.7) (Barreca et al., 2020).
Polyphenols found in terrestrial and marine environments have certain similarities, but
their chemical structures are fundamentally distinct from one another. Polymers that are
derived from avonoids or gallic acids are known as terrestrial polyphenols. Brown algae
are the only known source of the marine polyphenol phlorotannins, which are themselves
polymers of phloroglucinol (1,3,5-trihydroxybenzene). Inhibitory effects of a crude extract
of phlorotannins from brown algae on HAase were observed. Two polyphenols (E. bicyclis
and E. kur ome) with IC50 values four times higher than an antiallergic drug are called crude
phlorotannins (DSCG) (Giddings and Newman, 2022).
13.10.2 POLYSACCHARIDES
In recent years, seaweed-derived polysaccharides have garnered increasing attention from the
healthcare and pharmaceutical industries. Algal polysaccharides include, but are not limited
to, carrageenans, alginates, and agar. Cell walls of certain species of red algae, particularly
those of genera Gelidium and Gracilaria, contain agar. It is a prime structural component
of algal cell walls. Carrageenans are galactan polysaccharides that are made up of galactose
residues linked together in alternating 1, 3- and 1, 4-linked chains. They are found in seaweeds
and are responsible for filling the gaps between the cellulose plant components.
Sulfated components make up the majority of the active components that are found
in algal polysaccharides. The majority of research points in the direction of sulfated
polysaccharides being able to boost the innate immune response. This is accomplished
by encouraging macrophages and natural killer cells to engage in tumoricidal activities.
Tumor antigen is transported by antigen-presenting cells, which migrate in and out of
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FIGURE 13.7 Anticancer polyphenolic molecules from marine floras.
Source: Reprinted with permission from Kim and Himaya (2011). Copyright © 2011 Elsevier Inc.
⏎
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tumors to produce T-helper cell-stimulating cytokines such as interleukin-1 beta and
tumor necrosis factor alpha. Cancer progression is also inuenced by antigen-presenting
cells. This is because T-helper cells promote the proliferation of cytotoxic T-cells, which
kill cancer cells effectively. Cytotoxic T-cells target tumor cells. With the promotion of
such a mechanism, sulfated polysaccharides have the potential to boost adaptive immune
response. Sulfated polysaccharide has the ability to attach to CD2, CD3, and CD4 on
the surface of T lymphocytes, which in turn boosts the T-cells’ proliferative response.
The apoptosis of pancreatic islet cancer may be induced by PI-88, which is a sulfated
oligosaccharide. Internalized sulfated glycosaminoglycans (GAGs) disrupt the activity
of transcription and, as a result, cause melanoma cells derived from mouse models to
undergo apoptosis (Parthasarathy et al., 2020).
Brown algae produce fucoidan, a type of sulfated polysaccharide, in their cell walls.
Sulfated L-fucose is its main ingredient. The biological effects of fucoidans range from
providing mechanical support to signicantly altering cellular processes or binding
proteins. Fucoidans participate in cell adhesion, migration, proliferation, and differentiation in a manner similar to that of GAGs. In addition to this, they have the potential to
inuence therapeutically relevant processes such as atherosclerosis, the dissemination of
tumor cells, and angiogenesis. Fucoidans, in comparison to other sulfated polysaccharides, have been the subject of a greater amount of research in recent years in the hopes of
developing treatments or foods with benecial properties (Giddings and Newman, 2022).
13.10.3 ALKALOIDS
The term “alkaloid” is used to describe a wide range for biological amines-related compounds,
some of which contain halogenated cyclic nitrogen. The latter is something that can only be
found in aquatic organisms, such as marine algae, and cannot be found in plants that grow
on land. There have been a number of studies conducted on the chemistry of alkaloids and
the anticancer effects they possess in terrestrial plants; however, there have been relatively
few studies conducted on marine plants. According to Kappelmeier, the first alkaloid to
be isolated from a terrestrial plant was morphine in the year 1805, while the first alkaloid
to be identified in a marine alga was hordenine in the year 1969. The most well-known
anticancer alkaloids are camptothecin and its derivatives, which are currently the subject of
clinical studies. Homoharringtonine is an alkaloid that has been shown to be useful against
various types of leukemia; it is perhaps produced from the Chinese tree Cephalotaxus
harringtonia (Cephalotaxacea). In addition, the Sangre de Grado plant’s alkaloid taspine
hydrochloride is being studied as a possible anticancer treatment (Parthasarathy et al.,
2020). In Madagascar, Catharanthus roseus vinca alkaloids like vinblastine and vincristine
were first discovered. These medicines were put through their paces in early clinical trials in
the war against cancer. Blood cancer, lymphomas, advanced testicular cancer, breast cancer,
lung cancer, and Kaposi’s sarcoma can all be treated with vinblastine and vincristine in
combination with other chemotherapy medicines. The alkaloids found in marine plants can
be either phenylethylamine or indole. The biological effects of these alkaloids have not
been thoroughly investigated. Research on marine pharmaceuticals has mostly focused on
the development of novel medicines for the treatment of cancer as its primary objective. A
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red alga was the source of the discovery of two derivatives known as lophocladine A and
lophocladine B. It has been shown beyond a reasonable doubt in a variety of cancer cell lines
that Lophocladia sp., which was discovered on Fijian Island in New Zealand, had anticancer
properties (Parthasarathy et al., 2020) (Figure 13.8).
FIGURE 13.8 Anticancer alkaloids from marine flora.
Source: Reprinted from Boopathy and Kandasamy (2010). https://creativecommons.org/licenses/by/4.0/
⏎
Coastal mangroves have cancer-ghting alkaloids in their make-up. The alkaloid
“Rhizophrine” is abundant in the foliage of Rhizophora mucronata and Rhizophora stylosa.
Acanthus illicifolius has been shown to contain acanthicifolin, Bruguiera sexangula contains
the sulfur-containing alkaloid brugine, and Aegicerascorniculatum and Kandeliakandel both
contain the benzoquinones. These compounds were found in similar proportions in each plant.
13.11 OTHER MARINE SOURCES FOR ANTICANCER COMPOUNDS
Rhodophyceae, Phaeophyceae, and Chlorophyceae are the three families that make up the
kingdom of algae. Algae are classified as photosynthetic polyphyletic creatures. Macroalgae
have a fast growth rate in the open ocean, which results in a substantial amount of biomass
being produced. In addition to the virtue of not being dependent on land or water, the photosynthetic activity of macro-algae is far greater than that of terrestrial biomass. Their striking
red hue may be attributed to the high level of phycoerythrin. Red seaweed has the ability to
digest starch, which is analogous of linear amylose and highly branched amylopectin and
may be used as food reserve. The phrase “brown algae” refers to a sort of multicellular algae
species thrives in the sea and comes in a range of various forms and sizes. Although some
may reach a length of 60 m in length, others are just a few millimeters long. Carbohydrates
make up more than half of the dry biomass of brown algae, which indicates that this kind of
algae has high carbohydrate content. Large volumes of brown algae are cultivated for the
purposes of food production and alginate extraction (Al-Rajhi et al., 2022).
13.11.1 PEPTIDES
Peptides of a wide variety of types have been extracted from several distinct types of
maritime plants. In the last 10 years, researchers have found more than 2500 new peptides
that have an activity that inhibits cell proliferation. When exposed to pure peptides, a wide
variety of human cell lines exhibited cytotoxic effects. These cell lines included those
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derived from the pancreas, breast, bladder, and lungs. The cyclic depsipeptide known as
apratoxin A was responsible for the death of human HeLa cervical cancer cells via its effect
on the cell cycle. Both the cyclic Depsipeptides Coibamide A and the cyclic Depsipeptides
Lyngbyabellin B obtained from Leptolyngbya sp. and Lyngbya majuscule, respectively,
were shown to have a comparable action mechanism. It has been determined that Symploca
sp. are the source of linear pentapeptides known as Dolastatin 10 and Symplostatin 1.
Phosphorylation of Bcl-2 and activation of caspase-3 have been proven to be mechanisms
responsible for their potentially fatal effects on human lung and breast cancer cell lines. In
addition, several species of Lyngbya and Nostoc have been identified to have a wide range
of active peptides. It has been shown that these active peptides may inhibit cell proliferation by interfering with secretory pathways, causing disruptions in microfilaments, and
engaging in a variety of other intracellular processes (Santos et al., 2020).
Sansalvamide A is a specialized type of cyclic depsipeptide. It was isolated from a wide
range of marine fungi. Cancers of the breast, pancreas, colon, and prostate have all been
demonstrated to be susceptible to the cytotoxic effects of this chemical. This offers hope
for the development of new cancer treatments. Despite the fact that the particular mechanism of action of this depsipeptide is unknown, the allosteric impact of A’s attachment to
HSP90’s N-middle domain, which is necessary for the development of tumors, prevents
the creation of protein complexes (Al-Rajhi et al., 2022) (Figure 13.9).
FIGURE 13.9 Anticancer peptides from marine organisms.
Source:
Reprinted from Khalifa et al. (2019). Copyright © 2019 by the authors. Licensee MDPI, Basel,
Switzerland. http://creativecommons.org/licenses/by/4.0/.
⏎