Review

Recent Advancement in Anticancer Compounds from Marine

Organisms: Approval, Use and Bioinformatic Approaches to
Predict New Targets
Giovanna Santaniello 1, Angela Nebbioso 1, Lucia Altucci 1,2,3,* and Mariarosaria Conte 1,*

1 Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Vico L. De Crecchio 7,

80138 Naples, Italy
2 BIOGEM, Institute of Molecular Biology and Genetics, Via Camporeale, 83031 Ariano Irpino, Italy

3 IEOS, Institute for Endocrinology and Experimental Oncology, CNR, Via Pansini 5, 80131 Napoli, Italy

* Correspondence: [email protected] (L.A.); [email protected] (M.C.);

Tel.: +39-081-5667564 (M.C.)

Abstract: In recent years, the study of anticancer bioactive compounds from marine sources has
received wide interest. Contextually, world regulatory authorities have approved several marine
molecules, and new synthetic derivatives have also been synthesized and structurally improved for
the treatment of numerous forms of cancer. However, the administration of drugs in cancer patients
requires careful evaluation since their interaction with individual biological macromolecules, such
as proteins or nucleic acids, determines variable downstream effects. This is reflected in a constant
search for personalized therapies that lay the foundations of modern medicine. The new knowledge
acquired on cancer mechanisms has certainly allowed advancements in tumor prevention, but un-
fortunately, due to the huge complexity and heterogeneity of cancer, we are still looking for a defin-
itive therapy and clinical approaches. In this review, we discuss the significance of recently ap-
proved molecules originating from the marine environment, starting from their organism of origin
to their structure and mechanism of action. Subsequently, these bio-compounds are used as models
Citation: Santaniello, G.; Nebbioso, A.;
to illustrate possible bioinformatics approaches for the search of new targets that are useful for im-
Altucci, L.; Conte, M. Recent
proving the knowledge on anticancer therapies.
Advancement in Anticancer
Compounds from Marine
Keywords: cancer; marine environment; bioinformatic tools; anticancer compounds; bioactive
Organisms: Approval, Use and
Bioinformatic Approaches to Predict
molecules; molecular mechanism
New Targets. Mar. Drugs 2023, 21,
24. https://doi.org/10.3390/
md21010024
1. Introduction
Academic Editor: Sergey A.
Dyshlovoy In recent years, cancer hallmarks have been constantly updated based on tumors'
increasingly complex characteristics. Among these, we can include an emerging hallmark,
Received: 24 October 2022
non-mutational epigenetic reprogramming, which represents another independent mode
Revised: 23 December 2022
of genome re-engineering. [1]. Cancer is a set of diseases that dynamically become more
Accepted: 23 December 2022
and more complex, making the search for effective therapies crucial [2,3]. Lately, several
Published: 28 December 2022
drugs used for the treatment of different types of tumors have been studied, approved
and re-proposed alone or in co-treatment. Many of these drugs are of marine origin and
are extremely effective for the therapeutic measures of other diseases. There are many
Copyright: © 2022 by the authors. Li- reasons that justify the strong interest for molecules of marine origin. Firstly, the sea is a
censee MDPI, Basel, Switzerland. huge source of biodiversity, and thanks to the great variability of conditions present in
This article is an open access article this environment, its inhabitants have developed many living adaptations. The numerous
distributed under the terms and con- environmental factors, such as temperature, pressure, pH, light exposure, salinity, gas
ditions of the Creative Commons At- presence, etc., influence the life of marine organisms also in terms of the complexity of
tribution (CC BY) license (https://cre- produced molecules [4,5]. Among the strategies to survive these kinds of ecological pres-
ativecommons.org/licenses/by/4.0/). sures, there is also the production of secondary metabolites, used as signaling molecules

Mar. Drugs 2023, 21, 24. https://doi.org/10.3390/md21010024 www.mdpi.com/journal/marinedrugs

Mar. Drugs 2023, 21, 24 2 of 27

as a form of communication, of defense/offense or for competition [6]. Therefore, the con-

cept of biodiversity offers a major variability regarding molecular interactions and bio-
chemical reactions, and thus, the production of new bioactive molecules that can be po-
tential anticancer drugs [7,8]. This is not enough: it is also crucial to maintain an eco-sus-
tainable marine environment that allows the preservation of these characteristics also in
socio-economic terms.
The known marine species, according to the World Register of Marine Species
(WoRMS), are about 240,000, and certainly, there are many more, including various kinds
of organisms: Animalia, Bacteria, Plantae, Protozoa, Archea, Fungi, etc., but the lack of
information does not allow us to trace their real number. From 2010 to date [9], several
marine drugs have been approved by the Food and Drug Administration (FDA) and other
world regulatory authorities for the treatment of various types of cancer derived from
different marine organisms such as: sponges (panobinostat and eribulin mesylate), tuni-
cates (plitidepsin, lurbinectedin and trabectedin) and the mollusk-associated cyanobacte-
ria (brentuximab vedotin; polatuzumab vedotin; enfortumab vedotin; belantamab
mafodotin; disitamab vedotin; and tisotumab vedotin) (Figure 1). Depending on their mo-
lecular targets and structural features, these compounds share different anticancer activi-
ties. Here, we describe the features of these compounds starting from the source and the
chemical structure to the different aspects of anticancer activity, also highlighted by the
several studies that describe their effectiveness. Starting from these premises, we also in-
vestigate potential biological activities related to approved marine molecules by predic-
tive bioinformatic criteria within anticancer therapies.
Mar. Drugs 2023, 21, 24 3 of 27

Figure 1. Approved marine drugs for cancer treatment and their organism of origin. (a,b) Structures
and names of compounds derived from marine sponges; (c,d) structure and names of compounds
obtained from tunicates; and (e) structures of molecules obtained from the relationship between
mollusks and cyanobacteria with specific associated monoclonal antibodies.

2. The Evolution of Phenotypic Plasticity in the Marine Environment

Phenotypic plasticity is a phenomenon highly enhanced by environmentally induced
alteration [10].
Some modifications induced by the environment can influence gene expression and
can be also transmitted from a generation to another by a memory mechanism [11,12].
This environmental information makes it possible to respond more quickly to habitat
disturbances and represents an adaptative strategy. In particular, organisms that inhabit
ecological niches subjected to greater variability are endowed with a greater phenotypic
plasticity response both in morphological and physiological terms [13]. There is no direct
connection between environmental input and phenotypic output, so phenotypic plasticity
cannot always be considered a measure of the reaction norm of an organism. Sessile ma-
rine organisms, such as sponges, corals or algae, adapt in the best way to phenotypic plas-
ticity compared to motile organisms through the generation of development variants ca-
pable of improving “fitness” generated by the so-called stressors. The study and under-
standing of all these molecular mechanisms are the basis of new advanced biotechnologies
as well as omics and bioinformatics studies. A deeper knowledge of these approaches is
at the basis of drug discovery, whose success is closely related to the prediction of new
targets and targeted bioassays characterization, as well as high-throughput chemistry.

3. Approved Anticancer Compounds from Marine Sponges

Marine sponges belong to the Porifera phylum, and the known species are more than
9000, which are divided into four classes: Calcarea, Demospongiae, Hexactinellida and
Homoscleromorpha [14]. To date, more than 5300 natural compounds have been isolated
from sponges or their associated bacteria, and this number is constantly updating [15].
Like other sessile marine species, these organisms have developed biological adaptations
to live in this habitat and survive predation or fouling by surrounding organisms. The
Mar. Drugs 2023, 21, 24 4 of 27

production of secondary metabolites is an important strategy to react to all these condi-

tions, and many of these bioactive compounds can be exploited for human needs [16].
From the beginning of the age of marine biodiscovery in the 1960s, some bioactive
compounds have been found and approved from marine sources. Among them, the oldest
have been isolated from the sponge Tethya crypta: the Cytarabine ARA-C discovered in
1959 by Walwick at the University of California used for leukemia and active on DNA
polymerase, and the Vidarabine ARA-A is instead an antiviral, which targets viral DNA
polymerase used for the first time for the treatment of Herpes simplex infection [17].
In the following subsections, we will describe the two most recent approved anti-
cancer drugs related to marine sponges (Table 1 and Supplementary Tables S1 and S2).
These compounds are both synthetic analogues–derivatives, which have been developed
from natural lead molecules found in these organisms. The possibility to generate other
synthetic molecules harboring better pharmacological activity is of extreme importance
because these sessile organisms are subjected to continuous biological variability due to
abiotic and biotic environmental changes [18].

3.1. Eribulin Mesylate

Eribulin mesylate (E7389, Halaven®, Eisai Inc., under license from Eisai R&D Man-
agement Co., Ltd. © 2022 Eisai Inc. HALA-US3824; us.eisai.com) is the simplified synthetic
analog of halichondrin B, a molecule isolated for the first time from the marine sponge
Halichondria okadai belonging to the Demospongiae class and known for the production of
okadaic acid [19]. The cytotoxic activity of halichondrin B was firstly detected in murine
models of solid tumors and leukemia, but the low yields obtained from the sponges lim-
ited its use [20]. Thanks to the production of synthetic halichondrin B, it was possible to
obtain many analogs, such as eribulin mesylate, that are formed by the typical right-hand
lactone ring of macrolides, but with the loss of the side chain replaced by a primary amine
(Figure 1a). This analog has an optimal activity harboring the original cytotoxic effect of
halichondrin B. Eribulin is currently used in clinical approaches for metastatic breast can-
cer (MBC). In 2010, it was approved in the USA by the FDA as Halaven®, and in 2011, the
European Medical Agency (EMA) approved its treatment for patients with locally or ad-
vanced MBC after two prior anthracycline- and taxane-based regimens [21].
This approval is based on a phase III clinical trial (NCT02753595), named EMBRACE,
which showed an overall survival advantage of 55% in patients treated with this molecule
compared to those that received standard therapy. In 2016, eribulin was also approved by
the FDA for the treatment of metastatic liposarcoma and leiomyosarcoma in patients who
received a prior anthracycline-containing regimen [22]. A cohort study called ESEMPiO
verified the efficacy and safety of eribulin by collecting data from 39 participating centers
in Italy including more than five hundred patients that received at least one eribuline
treatment. This study confirmed the outcomes observed in the clinical trials, maintaining
expected clinical activity and respecting a tolerable safety profile [23]. Eribulin elicits an-
ticancer activity via mitotic and non-mitotic mechanisms of action. It prevents the for-
mation of mitotic spindle-blocking cells in the G2-M phase by inducing apoptosis, but it
interferes also with tubulin polymerization suppressing the growth phase of microtubules
[24]. Its microtubule-depolymerizing mechanism differs from other tubulin-targeting
drugs for several reasons. First of all, it does not affect the shortening phase of tubulin like
other vinca alkaloids, but it acts on the growth phase and also binds a higher affinity site
compared to taxanes [25]. The resulting studies also showed a different response in the
tissues treated with eribulin compared to classical microtubulin-targeting agents; in par-
ticular, different effects on peripheral nerves, angiogenesis, vascular remodeling and epi-
thelial-to-mesenchymal transition were detected, affecting differently the tumor microen-
vironment [26].
Mar. Drugs 2023, 21, 24 5 of 27

3.2. Panobinostat
Panobinostat (LBH-589, Farydak®, Novartis Pharmaceuticals Corporation East Han-
over, New Jersey 07936) is a synthetic analog of Psammaplyn A, which was discovered in
1987 from a Tonga marine Demospongia firstly named Psammaplin aplysilla and then re-
vised with the current name Pseudoceratina purpurea [27]. Subsequently, it was also found
in other species and was soon identified as a promising molecule sharing a great variety
of biological activities ranging from antibacterial, antiviral, insecticidal to anticancer ac-
tivities (Supplementary Table S1) [28–33]. Psammaplyn A is formed by two symmetrical
bromotyrosine structures bonded by a disulfide bridge (Figure 1b). After its discovery,
many derivatives were found with different substituent groups, such as psammaplyn B-
D and biprasin[34] and psammaplyn E–J [35,36]. The synthetic production of these com-
pounds intensified the research on their potentialities and applications while also consid-
ering that, generally, marine organisms cannot be harvested in a massive way to extract
compounds.
Panobinostat shares cytotoxicity towards different cancer cell lines such as triple-neg-
ative breast cancer, endometrial and prostate cancers [37–39], as well as on multiple mye-
loma (MM) cells [40]. The wide anticancer activity of this drug is due to the effects on
many key enzymes involved in different important biological mechanisms in cancer cells:
DNA replication and transcription, the regulation of apoptosis, invasion and differentia-
tion. Panobinostat plays an important role in epigenetic regulation involving histone
deacetylase (HDAC) and DNA methyltransferase (DNMT) activities [35,39]. It acts as a
deacetylase inhibitor able to modulate class I, II and IV of HDAC enzymes by increasing
histone and non-histone proteins acetylation, thus, affecting the interactions with tran-
scriptional factors and resulting in the alteration of their functions and the expression of
specific genes. The effect of panobinostat in cancer cells has been attested through the
acetylation of α-tubulin or HSP90; both events are mediated by the inhibition of HDAC6,
influencing the tubulin dynamics and cell motility, as well as affecting the degradation of
pro-growth proteins [41,42]. These cumulative effects lead to the inhibition of cellular pro-
liferation and cell-cycle arrest or apoptosis in malignant cells [43]. Another important ac-
tion of panobinostat in cancer cells is the inhibition of aminopeptidase N, which is in-
volved in different processes, such as proliferation, angiogenesis and tumor invasion
[31,44]. Following the PANORAMA-1 phase III trial (NCT01023308), the FDA approved
panobinostat in 2015 for patients with relapsed or refractory MM in combination with
bortezomib and dexamethasone and after two previous therapeutical regimens. The clin-
ical trial showed an increase in the survival rates in patients treated with panobinostat,
corresponding to 5.5 months more, in terms of time, if compared to the untreated group
[45] (Table 1 and Supplementary Table S2).

Table 1. Drugs approved as anticancer compounds obtained from marine sponges: details about
sponge species, kind of compound and targets in cancer cells.
Compound Name Chemical Class Marine Source Species Mechanism of Action References
Eribulin mesylate Macrolide Sponge Halichondria okadai Interfering tubulin polymerization [21,22,24,26,46–48]
HDAC inhibitor [40,43,45,49–51]
Hydroxamic acid
Panobinostat Sponge Pseudoceratina purpurea Aminopeptidase-N inhibitor [44]
derivative
DNA Methyltransferase inhibitor [35]

4. Approved Anticancer Compounds from Marine Tunicates

Urochordata, commonly named Tunicates, are a sub-phylum of Chordata divided
into five classes, among which the Ascidiacea is represented by 3000 known species, and
according to taxonomists, there are more than 1500 species not yet classified [52]. These
organisms populate all marine habitats from the low to the deep sea and present a great
tolerance to different climate conditions. The huge biodiversity of organisms is connected
to a peculiar capability to adapt to different environmental variations and to produce
Mar. Drugs 2023, 21, 24 6 of 27

bioactive compounds; to date, there are more than 1200 distinct products characterized in
Ascidians [53].
In the following subsections, we will describe the latest three approved drugs from
two species belonging to Ascidiacea class (Table 2 and Supplementary Table S2). These
organisms are characterized by a very small genome and a short life cycle, distinctions
which make them very attractive for developmental biology. For these reasons, there is a
strong effort to characterize new species and new molecules to understand their pharma-
cological potential.

4.1. Plitidepsin
Plitidepsin (Aplidin®, PharmaMar, S.A., Colmenar Viejo, Spain) is a cyclic depsipep-
tide, isolated for the first time in 1991 from the Mediterranean tunicate Aplidium albicans,
and belongs to didemnins, a group of molecules studied for their cytotoxic effects (Figure
1c) [54]. Another member of this family is the didemnin B, previously found in the Carib-
bean Trididemnum solidum, but due to its neuromuscular toxicity, studies were stopped,
preferring the well-tolerated and more active plitidepsin. The difficulty to harvest and
cultivate the organisms slowed down the studies, even if the anti-tumor activity was really
interesting [55,56]. Nowadays, thanks to a deeper knowledge of aquaculture systems and
cultivation methods and a fine use of the multi-step total synthesis processes, it is easy to
produce this depsipeptide, preserving the marine ecosystem.
The activity of plitidepsin is related to the interaction with the eucaryotic Elongation
Factor 1 Alpha 2 protein (eEF1A2), which induces early oxidative stress, causing the rapid
activation of c-Jun N-terminal kinase (JNK) and p38/MAPK, leading, finally, to apoptosis
[57]. Plitidepsin has been studied for many kinds of cancer, and a promising activity has
been detected in the therapeutical approach for MM due to the overexpression of eEF1A2
in affected B cells [58,59]. Plitidepsin was approved in 2018 for refractory MM by the Aus-
tralian Therapeutic Goods Administration. The phase III (NCT01102426) clinical study,
ADMYRE, applied this therapy after the combined use of dexamethasone and at least
three prior regimens [60]. The use of this molecule is not extended to other countries be-
cause the benefits of the therapy have been considered limited for its side effects, but in
2021, the European General Court annulled the EMA’s previous refusal for market au-
thorization and activated another ongoing judgment of the therapy [61]. Some evidence
and trials have analyzed the potential use of plitidepsin as a candidate for the treatment
of COVID-19 in specific patients, but this approach needs further investigation [62,63].
Anyway, a case report study recently indicated plitidepsin as a successful treatment for
prolonged viral SARS-CoV-2 replication in a patient previously affected by chronic lym-
phocytic leukemia (CLL). The mechanism of action involved the inhibition of elongation
factor 1α (eEF1A) by plitidepsin, which prevents the expression of SARS-CoV-2 nucle-
ocapsid (N) protein [64].

4.2. Trabectedin
Trabectedin (Yondelis®, PharmaMar, S.A., Colmenar Viejo, Spain) was firstly iso-
lated after the NCI screening program of marine natural products in the 1960s by the Car-
ibbean tunicate, Ecteinascidia turbinata, but later, it was assessed that its production was
due to the associated microorganism Candidatus Endoecteinascidia frumentensis [65]. This
molecule is an alkaloid, structurally complex and rarely found as a product of marine or-
ganisms. Its structure is composed of two rings of tetrahydroisoquinoline (THIQ) fused to
another through a lactone bridge, and the full elucidation of this complex structure (Figure
1d) was defined with strong efforts, taking 20 years of studies since its discovery [25,66].
The cytotoxic activity of trabectedin towards cancer cells is given by its interaction with
the DNA. The huge molecule alkylates the DNA in the minor groove interfering with pro-
teins and transcription factors and also with molecules involved in DNA repairing pro-
cesses; as a consequence, there is a perturbation of the cell cycle and induction of apoptosis
[67]. An in vitro study analyzed the effect of trabectedin on cancer cell lines by studying
Mar. Drugs 2023, 21, 24 7 of 27

the block of RNA polymerase II during elongation. Following transcription, RNA Pol II
collides with the trabectedin, reducing the possibility of its movement along the strand.
This block causes the ubiquitination of the RNA transcript and induces its degradation via
proteasome [68,69].
Trabectedin also induces structural DNA modifications that can affect the recognition
of transcriptional factors to specific GC sequences; an example is the inhibition of the bind-
ing of TATA-Box Binding Protein (TBP), E2 factor (E2F) and nuclear transcription factor
Y (NF-Y) causing the inhibition of the expression of the multidrug exclusion pump,
MDR1, associated with chemoresistance [70–72].
Another clinical relevance in patients affected by myxoid liposarcomas is the ability
of trabectedin to displace the oncogenic transcription factor called FUS-CHOP from its
target sequence. This interaction leads to the derepression of the adipocytic differentiation
process, revealing an important advantage for the therapy of this kind of cancer [73].
Trabectedin had its first regulatory approval in 2007 from EMA as therapy for pa-
tients affected by advanced soft tissue sarcoma after failure of anthracyclines or ifosfamide
regimens (NCT01299506). The FDA approved trabectedin therapy in 2015 for liposarcoma
and leiomyosarcoma after prior treatment with anthracycline (NCT01343277) [74]. This
drug is very effective for liposarcoma treatment, and studies showed a strong reduction
in the risk of cancer progression.
Another way for trabectedin to affect cancer progression is related to the reduction
in tumor-associated macrophages (TAM). The strong presence of macrophages in solid
tumors, as in breast cancer, enhances tumor growth and the progression of metastasis.
Trabectedin reduces the presence of macrophages with an indirect anticancer activity, af-
fecting the tumor microenvironment [75,76].
Some studies also revealed that the use of trabectedin at low concentrations inhibits
the production of pro-inflammatory mediators, such as VEGF, IL6, etc., highlighting its
role in cytokines and chemokines modulation [75,77].

4.3. Lurbinectedin
Lurbinectedin (ZepzelcaTM, PharmaMar, S.A., Colmenar Viejo, Spain) is another al-
kaloid that originates from Ecteinascidia turbinata. Its structure differs in the composition
of the C ring of THIQ, which is replaced by a tetrahydro-β-carboline (Figure 1d). This
compound exhibits tumor-inhibiting activities toward metastatic small-cell lung cancer
and, in 2020, received FDA approval for patients who received platinum-based chemo-
therapy (NCT02566993) [78].
The mechanism of action is similar to trabectedin: the drug binds to DNA in the mi-
nor groove along GC-rich sequences, interfering with transcription and with repair pro-
cesses. Despite this, there is the formation of adducts that cause a cascade of events that
affects the activity of DNA-binding proteins, transcription factors and repair pathways,
leading to eventual double-strand breaks and cell death [79].
Lurbinectedin can also inhibit the binding of transcription factors to DNA. EWS-FL1
is an oncogenic transcription factor expressed in pediatric Edwing sarcoma, and it also
drives other different kinds of tumors. Xenograft models showed that lurbinectedin can
functionally inactivate EWS-FL1, modifying its distribution inside the nucleus and its ac-
tivity [80]. Lurbinectedin and trabectedin are two derivatives of the same molecule, and
their action on cells is very similar, they have two ways to operate their anticancer activity.
The first one is the alkylation of DNA characterized by the physical interaction between
DNA sequences and the drug, an event strictly connected to the occurrence of DNA dam-
age and strand breaks leading to cell death. A second mechanism involves the interference
between DNA interaction and transcription factors by selectively affecting tumor devel-
opment [81]. Similar to trabectedin, lurbinectedin can decrease tumor-associated macro-
phages by altering the tumor microenvironment [67].
Mar. Drugs 2023, 21, 24 8 of 27

Table 2. Drugs approved as anticancer compounds obtained from marine tunicates: details about
species, kind of compound and targets in cancer cells.
Compound
Chemical Class Marine Source Species Mechanism of Action References
Name
Ecteinascidia turbinata/ Alkylation of DNA [79]
Lurbinectedin Alkaloid Tunicate/bacteria Candidatus Inhibition of the transcriptional factors
[80,81]
Endoecteinascidia frumentensis binding to DNA
Block RNA Pol-II [68,69]
Ecteinascidia turbinata/
Inhibition of the transcriptional factors
Trabectedin Alkaloid Tunicate/bacteria Candidatus [70–72]
binding to DNA
Endoecteinascidia frumentensis
Reduction in TAM [75,76]

Plitidepsin Peptide Tunicate Aplidium albicans Activation of eEF1A2 [55,82–84]

5. Approved Anticancer Compounds from Mollusks/Cyanobacteria Association

In the last ten years, many antibody–drug conjugates (ADCs) have been approved,
starting from molecules isolated from the symbiosis of cyanobacteria and mollusks (Table
3 and Supplementary Table S2)
The number of Molluska marine species is currently estimated over 50000, while cy-
anobacteria cover over 1600 species and, following some prediction studies, are estimated
to be more than 6000 [85,86]. Cyanobacteria embrace lots of symbiotic associations with
different marine organisms such as Porifera, Cnidaria, Molluska, Macroalgae, etc., and
these symbioses can produce secondary metabolites and also toxins showing bioactivities
that can be useful for various treatments, including cancer [87].
The analysis of the symbiotic association between these organisms is really interest-
ing, considering also that knowledge about cyanobacteria biosynthetic potentialities is
limited, and many of their genomes have not been yet sequenced. Because the exchange
of infochemicals is constantly altered, a deeper understanding of chemical ecology cou-
pled with biotechnological advancements could help to acquire more in-depth
knowledge.
Thanks to the latest generation technologies, all this is becoming more possible, but
certainly, we are still very far from the possibility of being able to somehow standardize
the beneficial effects that arise from the association of these marine organisms

5.1. Brentuximab Vedotin

Brentuximab vedotin (SGN-35, Adcetris®, Seagen Inc., Bothell, Washington, USA)
leads to another class of anticancer compounds recently approved deriving from dolas-
tatins, linear pentapeptides isolated less than 40 years ago from the sea hare, Dolabella
auricularia, a mollusk from the Indian Ocean [88]. After the discovery of the active com-
pound, it was clear that its production was due to the presence of two cyanobacteria pre-
sent in the mollusk-based diet, namely, Symploca hydnoides and Lyngbya majuscula, mem-
bers of the order Oscillatoriales [89–91].
Due to the toxic effect exhibited by dolastatins, the same studies for structural modi-
fications were necessary to exploit their cytotoxic potentialities [92]. Auristatins are deriv-
atives of dolastatins, composed of four amino acids with different modifications at the C-
terminus. Mono-Methyl auristatin-E (MMAE) and Mono-Methyl auristatin-Phe (MMAF)
are the most representative among studied drugs, modified respectively with Norephed-
rine and phenylalanine at their C-termini [93]. These molecules have been associated with
monoclonal antibodies, allowing their use as antibody–drug conjugates (ADCs), to better
exploit their activity (Figure 1e). In this way, the cytotoxic effect is highly specific and
directed to the cells that expose the correct antigen [94].
The mechanism of action is common for all the ADCs associated with auristatin. The
antibody recognizes the antigen present on the surface of the cancerous cell and then is
internalized through clathrin-mediated endocytosis. Once inside the cell, the lysosome
proteases cleave the linker and release the auristatin, affecting its cytotoxic activity.
Mar. Drugs 2023, 21, 24 9 of 27

The auristatin released in the cell acts as an anti-tubulin agent preventing its polymer-
ization, so cell division is inhibited, and apoptosis is induced [95]. These improvements in
the use of auristatin derivatives have been applied to many clinical trials for different
kinds of cancer diseases; especially, the use of chemo-labeled antibodies has been ap-
proved for several molecules.
Brentuximab vedotin is an example of the first commercially marine-derived ADC
used and was approved by the American FDA in 2019 for the treatment of patients af-
fected by Hodgkin’s lymphoma, systemic anaplastic large cell lymphoma or cutaneous
and peripheral T cell lymphomas (NCT01421667) [96].
This drug is formed by four conjugated molecules of MMAE, also defined as vedotin,
bonded via a protease-cleavable linker to the anti-CD30 antibody, normally expressed in
activated B and T cells. Its ligand, CD30, is rarely expressed in normal cells, but mainly
expressed in diseased cells of patients [97].

5.2. Polatuzumab Vedotin

Another approved ADC is Polatuzumab vedotin (PolivyTM, DCDS-4501A, Genen-
tech, Inc., San Francisco, USA). In this case, there are 3.5 MMAE molecules (quantity de-
fined following the DAR—drug-to-antibody ratio) associated with CD79b [98]. This anti-
gen belongs to the B cell receptor complex, and its ligand is highly expressed in lymphoma
patients’ B cells; moreover, its activation involves the downstream signaling of BRC [99].
This drug was approved by the FDA in 2019 for the treatment of diffuse large B cell lym-
phoma in combination with two prior therapies including rituximab and bendamustine
[100]. This therapy is highly specific and was approved after a phase Ib/II study
(NCT01992653) on ineligible patients for transplantation and with previous failure treat-
ment with standard therapies [101].

5.3. Enfortumab Vedotin-eifv

Enfortumab vedotin-eifv (Padcev®, AstellasPharma & Seagen Inc., Bothell, Washing-
ton, USA) is on the market for the treatment of metastatic or locally advanced urothelial
cancer. This therapy was approved by the FDA in 2019 after a phase II trial (NCT03219333)
for patients that previously received treatment with a platinum regimen and with inhibi-
tors of programmed cell death (PD-1) and programmed death ligand 1 (PD-L1) [102]. The
molecule is structurally formed by 3.8 molecules of MMEA—a linker—and the antibody
targeting Nectin-4—a transmembrane protein characteristic of epithelial cancers—and
used as specific target for Nectin-4-positive urothelial cancer [103]. The approval of enfor-
tumab arrived on April 2022, also in Europe after USA approval, following a phase III trial
(NCT03474107) that confirmed a higher overall survival for treated patients of about 4
months [103].

5.4. Disitamab Vedotin

Another approved ADC formed by vedotin is the Disitamab vedotin (AidixiTM,
RemeGen, Yantai, China). This molecule is associated with the human epidermal growth
factor receptor-2 (HER-2) antibody involved in the regulation of cell duplication, prolifer-
ation and apoptosis [98] . Since several cancers are HER-2-positive, the antibody present
in this molecule is used as a target for anticancer compounds. In this case, anticancer ac-
tivity is explicated in two different ways: one is the inhibition of signaling pathways acti-
vated by HER-2; the other one is operated by MMAE that acts, as mentioned before, as a
microtubulin inhibitor blocking mitosis [104]. Disitamab was approved in China by the
Chinese National Medical Products Administration for HER-2-positive locally advanced
or metastatic gastric cancer after a phase II study (NCT03556345) in patients who received
two prior chemotherapeutic treatments [105] .
There is also an ongoing phase II study to evaluate the therapeutical possibility of
this molecule for breast cancer, comparing the efficacy with different drug doses against
Mar. Drugs 2023, 21, 24 10 of 27

HER-2-positive and HER-2 low expression in cancer patients [106]. Urothelial cancer is
another typical HER-2-overexpressing cancer, and its response to disitamab has also been
evaluated [107] in a phase II study (NCT04264936) on patients with HER-2 locally ad-
vanced or metastatic urothelial cancer refractory to classical therapies, which showed
good overall survival and a promising efficacy with a manageable safety profile [108].

5.5. Tisotumab Vedotin-tftv

Tisotumab (Tivdak®, Seagen Inc., Bothell, Washington, USA) is a vedotin ADC asso-
ciated with a specific antibody for the tissue factor TF-011, also called thromboplastin. This
cell-surface glycoprotein is normally involved in blood coagulation but is also expressed
in many cancer types, such as cervical, ovarian and bladder cancers [109–112]. The role of
TF-011 in tumor progression is supposed to be related to its procoagulant activity and the
protease-activated receptor-2 (PAR-2) signaling pathway [113,114].
The cytotoxic activity of tisotumab is due not only to the effect of vedotin but also to
the capacity of the molecule to diffuse into the tumor microenvironment and to kill the
dividing cells. In this way, tisotumab can bind FCγRIIIa, present on bystander natural
killer cells, and leads to antibody-dependent cellular cytotoxicity [115].
Tisotumab was approved in 2021 by the FDA for the therapy of recurrent and meta-
static cervical cancer after the phase II InnovaTV 204 trial (NCT03438396) in patients that
received two prior systemic regimens, including platinum-based chemotherapy [116], and
the recruitment is now ongoing for the phase III trial, InnovaTV 301 (NCT04697628) [117].

5.6. Belantamab Mafodotin-blmf

Belantamab mafodotin-blmf (Blenrep® GlaxoSmithKline, Ireland) is a recently ap-
proved drug for the therapy of relapsed or refractory multiple myeloma (RRMM) in pa-
tients who received at least four therapies, including an immunomodulatory agent, an
anti-CD38 monoclonal antibody and a proteasome inhibitor. This therapy obtained regu-
latory approval from the FDA and EMA in 2020. The DREAMM-2 phase II trial
(NCT03525678) demonstrated a durable response to this therapy in RRMM patients. A
phase III study is still ongoing, and it will evaluate about 320 patients with more than two
prior lines of therapies, whereafter the results will be available in 2024 [118].
Belantamab mafodotin is composed of four molecules of MMAF as the cytotoxic part.
MMAF is also defined as mafodotin due to a phenylalanine aminoacidic residue that gives
different permeability characteristics to the compound.
The selected antibody for this ADC is IgG1k, which is specific for the antigen B cell
maturating agent (BCMA). In this case, there are two different mechanisms of action: one
is given by the effect of mafodotin, and the other is given by the antibody. This antibody
is particularly active because it is afucosylated, and this characteristic enhances the re-
cruitment of immune effector cells because afucosylation creates a higher binding affinity
for the receptor, FCγIIIaR, which is also involved in the interaction with the B cell. In this
way, the molecule can kill tumor cells by both antibody-dependent cellular cytotoxicity
and antibody-dependent cellular phagocytosis [119,120].

Table 3. Drugs approved as anticancer compounds obtained from mollusk-associated cyanobacte-

ria: details about species, kind of compound with associated antibody and targets in cancer cells.

Compound Name Chemical Class Marine Source Species Mechanism of Action References
Brentuximab ve- ADC Mollusk/ Dolabella auricolaria/ Microtubulin targeting
[95–97]
dotin (MMAE+CD30Ab) Cyanobacteria Symploca hynoides, Lyngbya majuscula agent via CD 30
Polatuzumab ve- ADC Mollusk/ Dolabella auricolaria/ Symploca Microtubulin targeting
[100,101,121]
dotin (MMAE+CD-79bAb) Cyanobacteria hynoides, Lyngbya majuscula agent via CD79
Enfortumab ve- ADC Mollusk/ Dolabella auricolaria/ Symploca Microtubulin targeting
[103,122]
dotin (MMAE+Nectin-4 Ab) Cyanobacteria hynoides, Lyngbya majuscula agent via Nectin4
Disitamab Mollusk/ Dolabella auricolaria/ Symploca Microtubulin targeting
MMAE+HER-2 Ab [105,107,108,123]
Vedotin Cyanobacteria hynoides, Lyngbya majuscula agent via HER-2
Mar. Drugs 2023, 21, 24 11 of 27

Dolabella
Tisotumab Mollusk/ Microtubulin targeting
MMAE+TF-011 Ab auricolaria/ Symploca hynoides, [113–116]
Vedotin Cyanobacteria agent via TF-011
Lyngbya majuscula
Belantamab Mollusk/ Dolabella auricolaria/ Symploca Microtubulin targeting
MMAF+CD38Ab [118–120]
mafodotin Cyanobacteria hynoides, Lyngbya majuscula agent via CD38

6. Prediction Bioinformatics Tools in Marine-Derived Compounds

Here, we evaluate the therapeutic significance of the molecules derived from marine
species described in the previous sections to subsequently identify further biological ac-
tivities that could be predictive for the study of the molecular mechanisms involved in
cancer progression.
The use of several tools and software connected to databases is an advantageous ap-
proach that avoids different issues, such as the expensive costs of screening or the time
spent to exploit the in vivo capabilities of compounds [124]. In silico methods are a valid
opportunity to analyze the possible activities of chemicals for a new vision of drug dis-
covery, which allows identifying the cytotoxicity of molecules or checking the activation
of specific metabolic pathways. It could represent a possibility to save time in research
study, giving an early result based on a prediction. This is a not dismissible point, consid-
ering the need for new drugs for several kinds of diseases.
One of the tools we used for these studies is PASS (Prediction of Activity Spectra for
Substances (http://www.way2drug.com/passonline/, accessed on 10 October 2022, a soft-
ware based on the Bayesian method that, starting from the structure of the molecule, can
give accurate and robust predictions about a possible bioactivity [125]. We used the SMILE
format (simplified molecular-input line-entry system), which expresses molecular formu-
las and reactions in line notation, adopting letters for the atoms, symbols (-, = or #) for the
bonds, enclosed parentheses for the branches and specific rules for cyclic and discon-
nected structures. The use of this language is very common because it is compact and
printable and takes less space than an equivalent connection table, also in terms of bytes
for the use of databases or software. There are different formats used to upload molecules
to these databases; one is SMILE, but MOL and Marvin JS files are commonly accepted by
these kinds of software, which represent, respectively, the table format and the image of
the structure of the studied molecule. These molecule formats are available in commonly
used databases, such as PubChem https://pubchem.ncbi.nlm.nih.gov/ (accessed on 10 Oc-
tober 2022, and it is also possible to use online converters to obtain the different formats
(such as https://cactus.nci.nih.gov/translate/, accessed on 10 October 2022. The different
ways to express the analyzed molecules is listed in Supplementary Table S3.
To give an example of the application of these bioinformatic tools, we selected three
of the molecules analyzed in the previous section, one for every marine origin group.
This kind of analysis matches data contained in different databases, starting from the
information present in the structure of the compound and also the knowledge available
in the literature. The first evaluation involved the activity spectrum of every single mole-
cule according to two distinct parameters defined by the software, considering the prob-
ability of being active (Pa) and the probability of being inactive (Pi).
We applied a cut-off of Pa > 0.5 to these values as a general parameter for all the
analyzed predictions. We also considered the use of another service related to PASS,
named CLC-pred (cell line cytotoxicity predictor), to predict the cytotoxic effect of a se-
lected compound in cancer and non-cancer cell lines. This information will drive the
choice of future target cancer cell lines to select the bioactivity of the drug-like compound
[124].
Another point we evaluated regarded the possibility of obtaining data related to the
clinical manifestations observed in patients, including toxic and adverse effects. Once
these parameters were identified using the DIGEP tool (prediction of drug-induced
changes in gene expression profiles) [126], DIGEP was connected to PASS by accessing an
external link and matching with different databases provided distinctive information
Mar. Drugs 2023, 21, 24 12 of 27

about the effects of the drug on cell metabolism and about the changes in gene expression.
Using different training sets, we identified differentially up-regulated and down-regu-
lated genes following the level of mRNA and expressed proteins after drug treatments.
The results were extrapolated matching the data present in the current literature; the
mRNA expression profiles were obtained by exploiting the mRNA training set of the tool,
composed of 1756 compounds, which allows one to predict the changes in gene expression
for 1802 genes.
The obtained data were further evaluated using a graphical gene set enrichment in-
teractive tool [127], wherein queried genes, using Ensembl code, were analyzed based on
gene ontology (GO) biological processes and molecular function, using ShinyGo (http://bi-
oinformatics.sdstate.edu/go/, accessed on 24 October 2022 by selecting the species homo
sapiens. In the following subsections, we will make an exemplary analysis of each com-
pound described for the corresponding kinds of organisms using these tools. Figure 2 pro-
vides a schematic representation of the bioinformatic tools used and the specific outcomes.

Figure 2. Schematic representation of the pipeline used for the bioinformatic predictions. Selected
compounds were analyzed with PASS online and ShinyGo, using three possible formats for the
analysis (SMILE, Mol file and Marvin JS). PASS online gives the first prediction about the activity,
and then, there are other additional services (CLC-pred and DIGEP-pre are the used ones). ShinyGo
is the other used tool for GO predictions.

6.1. Sponge-Derived Compound Prediction: The Example of Panobinostat

We added to the PASS database the structural formula of panobinostat by using
SMILE and launched the prediction. As expected, the data obtained showed a strong Pa
relative to the different classes of HDAC inhibitors, as confirmed by the vast evidence
already present in the literature and discussed in the previous dedicated section. We also
identified panobinostat-dependent activities as chemosensitizers and activators of the cal-
cium channel but with lower probability (Table 4). Anyway, recent studies have suggested
the use of panobinostat as a chemosensitizer in advanced ovarian cancer [128]. No signif-
icative data, instead, are reported concerning the activation of the calcium channel by
panobinostat.
Mar. Drugs 2023, 21, 24 13 of 27

Table 4. List of the predicted activities recognized by the PASS tool for panobinostat with the indi-
cated probability of being active and inactive from 0 to 1.
Activity Pa Pi
HDAC 1 inhibitor 0.843 0.001
HDAC class I inhibitor 0.842 0.001
HDAC inhibitor 0.792 0.002
HDAC 2 inhibitor 0.760 0.001
HDAC 4 inhibitor 0.706 0.001
HDAC IIa inhibitor 0.700 0.001
HDAC 8 inhibitor 0.530 0.001
Chemosensitizer 0.523 0.016
Calcium channel (voltage-sensitive) activator 0.521 0.064

We also predicted the toxic effects based on the possible clinical manifestations and
the different cancer cell lines, which could result from sensitivity to treatment by CLC-
pred. Panobinostat shared low Pa values for adverse effects such as ulcers or the presence
of occult bleeding, whereas considering the possible cancer lines sensitive to panobinostat
treatment, we mainly observed a Pa value of 0.784 for HCT-116 colon carcinoma cells (Ta-
bles 5 and 6). In particular, from the data obtained through the consulted databases, pano-
binostat-related possible cytotoxic effects were found in the colon cancer line, HCT-116,
as previously indicated and with regard to its combined effect and its safety profile. In
particular, the TRAIL-induced cytotoxic effect is enhanced by co-treatment with pano-
binostat in HCT-116 [129].
Considering the predictions made for the interaction with other cancer cell lines, we
observed that in the lung cancer cell line, NCI-H1299, panobinostat displayed a Pa = 0.543;
while in the triple-negative-resistant breast cancer line, the cytotoxic effect was detected
with a Pa = 0.518. Identified in silico predictions by PASS suggested that, despite the fact
that panobinostat was initially identified for the treatment of MM, it may be considered a
good candidate for the study and treatment of other diseases.

Table 5. Predictions of the possible clinical manifestations observed in patients following panobino-
stat treatment.
Possible Adverse and Toxic Effects Pa Pi
Ulcer, gastric 0.362 0.057
Occult bleeding 0.421 0.131
Ulcer, peptic 0.346 0.088

Table 6. Prediction of the possible cancer cell lines sensitive to panobinostat treatment related to
cytotoxic activity.
Cell Line Full Name and Code Tissue Pa Pi
Colon Carcinoma HCT-116 Colon 0.784 0.0070
Non-small cell lung carcinoma NCI-H1299 Lung 0.543 0.004

Using DIGEP as a prediction system we matched the genes involved in the metabolic
pathway activated by the drug, considering the data present in the comparative toxicoge-
nomics database (CDT). In Table 7, several up- and down-regulated genes are predicted
to be differentially expressed following panobinostat treatment. Notably, in a recent
study, the CTPS1 gene, which shares high Pa prediction in our analysis, was associated
with a lower survival outcome in plasma cell myeloma patients belonging to the high-risk
metabolic cohort [130]. This is very interesting information that can be extrapolated from
our prediction since panobinostat could represent a valid candidate for a better under-
standing of metabolic-based mechanisms linked to this disease.
Mar. Drugs 2023, 21, 24 14 of 27

Table 7. DIGEP predictions of panobinostat-regulated genes.

Down-Regulated Up-Regulated
Pa Pi Pa Pi
Genes Genes
CTPS1 0.875 0.001
INCENP 0.863 0.006
KEAP1 0.795 0.008
TACC1 0.833 0.004
AKR1C3 0.802 0.022
ITGAM 0.819 0.021
EIF4G2 0.700 0.003
H1F0 0.759 0.005
RCC2 0.697 0.002
HPGD 0.748 0.032
ABL1 0.676 0.002
FGF21 0.686 0.01
PHF11 0.683 0.013
TMSB4X 0.659 0.034
TOB1 0.715 0.050
OCLN 0.573 0.039
DHFR 0.701 0.048
SAT1 0.592 0.129
FABP4 0.664 0.049
MAPK4 0.563 0.114
NPM 0.568 0.137

Starting from the data obtained from the DIGEP predictions, the genes whose expres-
sion is influenced by the drugs were submitted to GO analysis. Data showed for ShinyGo
analysis are based on the analysis of normal cell lines in human models not treated with
the drug. Both up- and down-regulated genes were then analyzed by the ShinyGo tool in
order to identify possible predictive GO biological and molecular functions. For both GO
processes, we applied a false discovery rate (FDR) cut-off of 0.05. Data were represented
by each category name related to fold enrichment -log10 (FDR). As we can see in Figure
3A, the higher bar size is represented by the category of genes that regulate the cytoplas-
matic sequestering of transcription factors, suggesting that panobinostat selectively is able
to interact with specific transcription factors in the cytoplasm, which might be considered
a predictive effect of this molecule in this specific biological compartment. For example,
panobinostat is involved in the regulation of transcription factors present in the HOXA
cluster, which are under the control of the mixed-lineage leukemia (MLL) complex, whose
proteins are fused or mutated through interactions with many cofactors [131].
Mar. Drugs 2023, 21, 24 15 of 27

Figure 3. GO predictive analysis of differentially expressed panobinostat-related genes. (A) Biolog-

ical processes on queried panobinostat-dependent genes. Data show each pathway sorted by cate-
gory related to fold enrichment with -log10 (FDR) and applying an FDR cut-off of 0.05. (B) Molecular
functions on queried panobinostat-dependent genes applying an FDR cut-off of 0.05.

This demonstrates its role also in off-target interactions that can be identified through
predictive analyses and provide useful information to better understand the molecular
mechanisms underlying these regulations. We also identified that panobinostat-related
genes might be involved in specific molecular functions, which could also be predictive
for different in-depth studies. For instance, we identified genes involved in diamine N-
acetyltransferase, phenanthrene 9,10 monooxygenase, polyamine-binding and methotrex-
ate-binding activities (Figure 3B), which are all related to molecular reaction/interaction
networks involved in the metabolism. This could mean that a network-based approach
could be useful to correlate deregulated pathways and drug effects for a further redout in
individual metabolism. These predictions consist of several cellular activities that could
be carried out by panobinostat and could offer useful information for a future approach
for a better in-depth study of a selected disease.

6.2. Tunicate-Derived Compound Prediction: The Example of Plitidepsin

The same analysis was conducted on plitidepsin by predicting a high activity as an
immunosuppressant (Pa = 0.788) and also a glycopeptide-like antibiotic (Pa = 0.738),
Mar. Drugs 2023, 21, 24 16 of 27

general pump inhibitor (Pa = 0.649) and, as we know, an antineoplastic (Pa = 0.657) (Table
8). This marine cyclic peptide is a clear example of therapeutic switching, which is becom-
ing an increasingly used strategy for the identification of new uses of an approved drug,
despite the fact that, after a long time since its discovery, it has been repurposed for the
treatment of COVID-19 to answer a current need not evidenced before.

Table 8. List of the predicted activities recognized by the PASS tool for plitidepsin with the indicated
probability of being active and inactive from 0 to 1.
Activity Pa Pi
Immunosuppressant 0.788 0.006
Antibiotic glycopeptide-like 0.738 0.003
General pump inhibitor 0.649 0.014
Antineoplastic 0.657 0.034
CYP2H substrate 0.650 0.050
Antifungal 0.585 0.020
Antineoplastic (colorectal cancer) 0.548 0.010
Antineoplastic (colon cancer) 0.541 0.010
Xenobiotic-transporting ATPase inhibitor 0.524 0.009
Antibacterial 0.453 0.021

Analyzing the predictions of the possible adverse reactions and side effects belonging
to plitidepsin, we observed a high Pa value related to the category of movement disorders
identified as dyskinesia, as well as sleep disturbance, dyspnea and ataxia, with Pa values
ranging from 0.960 to 0.776 (Table 9).

Table 9. Predictions of the possible clinical manifestations observed in patients following plitidepsin
treatment.
Possible Adverse and Toxic Effects Pa Pi
Dyskinesia 0.960 0.004
Sleep disturbance 0.898 0.012
Dyspnea 0.892 0.006
Ataxia 0.776 0.013

Concerning the predictions of the cytotoxicity towards cancer cell lines, the tool iden-
tified relevant results for the lung carcinoma cell line, A549, and also for the colon adeno-
carcinoma, HT-29, cancer cell line (Table 10). Plitidepsin case studies on its activity to-
wards A549 and HT-29 are few; for example, an investigation was conducted to evaluate
the efficacy of the drug encapsulated in some polymers [132]. This tool also identified
possible cytotoxic activities in other cancer cell lines, such as breast (MDA-MB-231) and
lung (DMS-114) adenocarcinoma cells. Although studies on plitidepsin cytotoxic activity
in MDA-MB-231 cells have already been published, information on the activity of this
compound in the identified lung cancer line are not available in the literature. This pro-
vides us future important indications of the potential cytotoxic effect of this molecule for
the study and treatment of this different cellular system.

Table 10. Prediction of the possible cancer cell lines sensitive to plitidepsin treatment for cytotoxic
activity.
Cell Line Full Name and Code Tissue Pa Pi
Lung carcinoma A549 Lung 0.808 0.011
Colon adenocarcinoma HT-29 Colon 0.801 0.005
Breast adenocarcinoma MDA-MB-231 Breast 0.554 0.020
Lung carcinoma DMS-114 Lung 0.501 0.038

From the analysis with the DIGEP tool, we identified many up-regulated and down-
regulated genes with a high value of Pa (Table 11). These genes are highly depicted in
metabolic pathways such as those involved in glucose homeostasis. Remarkably, we iden-
tified TMEM41B, a transmembrane protein-coding gene involved in the host’s modulation
Mar. Drugs 2023, 21, 24 17 of 27

of viral RNA genome replication. This is further evidence of plitidepsin-related antiviral

activities since recent studies indicated TMEM41B as a pan-flavivirus host factor, which
is also crucial for SARS-CoV-2 infection [126].

Table 11. DIGEP prediction of plitidepsin-regulated genes.

Down-Regulated Up-Regulated
Pa Pi Pa Pi
Genes Genes
NSF 0.907 0.012
TMEM41B 0.823 0.009
ALDH18A1 0.879 0.015
C10ORF118 0.826 0.012
H6PD 0.782 0.019
FAM49A 0.756 0.041
SLC15A1 0.765 0.036
PLXNA2 0.751 0.047
MYBL1 0.739 0.040
HMGCR 0.637 0.035
BACE1 0.697 0.016
PSAP 0.635 0.055
SLC14A1 0.675 0.053
TXNDC9 0.542 0.025
TOB1 0.682 0.063
PLK3 0.595 0.092
VTN 0.605 0.036
FGF21 0.517 0.034
BARD1 0.636 0.120
C8ORF4 0.552 0.083
FKBP5 0.599 0.086
WIPI1 0.530 0.106
CTPS1 0.566 0.090
GPRC5A 0.507 0.087
HSPB11 0.501 0.053
NUCB2 0.523 0.105
TAGLN 0.516 0.088

Both up and down-regulated genes were analyzed by the ShinyGo tool in order to
identify possible predictive GO biological and molecular functions related to drug treat-
ment. For both GO processes, we applied less stringent data by a false discovery rate
(FDR) cut-off of 0.11. Data were represented by each category name related to fold enrich-
ment −log10 (FDR). As can be seen in Figure 4A, the higher bar size is represented by the
genes belonging to cellular response to glucose stimulus, suggesting that plitidepsin
might have a role in adaptative cellular responses such as those concerning glucose me-
tabolism. It is also known that plitidepsin can affect cellular metabolism by acting on cel-
lular glutathione homeostasis, converting glutathione in the reduced forms and altering
its control level mechanisms [130]. We also identified that molecular functions, such as
peptide–proton symporter, phosphotransferase and ganglioside binding activities have
been recognized as predictive for plitidepsin treatment. Because ganglioside, an anionic
lipids family, is also present in this case, we can appreciate a close correlation between the
plitidepsin and SARS-CoV-2 interaction by a mechanism involving the recognition of
spike proteins. A great deal of predictive data, concerning the role of plitidepsin in the
recently discovered COVID-19 pandemic, clearly suggest the importance of using in silico
approaches, which is also underlined by the consistent bioinformatics data that are con-
stantly updated, thereby allowing the consultation of recently added biological activities
of our molecule of interest.
Mar. Drugs 2023, 21, 24 18 of 27

Figure 4. GO predictive analysis on differentially expressed plitidepsin-related genes. (A) Biological

processes on queried plitidepsin-dependent genes. Data show each pathway sorted by category re-
lated to fold enrichment with -log10 (FDR) and applying an FDR cut-off of 0.11. (B) Molecular func-
tion on queried plitidepsin-dependent genes. Data show each pathway sorted by category related
to fold enrichment with -log10 (FDR) and applying an FDR cut-off of 0.11.

6.3. Mollusks/Cyanobacteria Association-Derived Compound Prediction: The Example of

Belantamab Mafodotin
Here, we discuss the last example, analyzing belantamab mafodotin. From the results
of the prediction, we observed high values of Pa, 0.823, related to immunostimulant activ-
ity but also interesting values with proteasome ATPase inhibitor, 0.774, and, as we ex-
pected, antineoplastic activity with a 0.729 Pa value (Table 12). As we can observe, this
compound also shares its activities in solid tumors and, specifically, in pancreatic cancer,
despite its approval for MM treatment. Considering the enormous complexity of cancer,
these features could be useful in investigating an off-target therapeutic role of this mole-
cule alone or in combination with other therapies.
Mar. Drugs 2023, 21, 24 19 of 27

Table 12. List of the predicted activities by PASS tool following belantamab mafodotin treatment
with the probability of being active and inactive from 0 to 1.
Activity Pa Pi
Immunostimulant 0.823 0.008
Proteasome ATPase inhibitor 0.774 0.007
Antineoplastic (non-Hodgkin's lymphoma) 0.729 0.003
Muramoyltetrapeptide carboxypeptidase inhibitor 0.636 0.021
Antineoplastic (solid tumors) 0.537 0.010
Peptide agonist 0.537 0.039
Neuropeptide Y4 antagonist 0.461 0.027
Antineoplastic (pancreatic cancer) 0.437 0.010
CYP2H substrate 0.502 0.122
Fibroblast growth factor agonist 0.419 0.056

The prediction for the toxic and adverse effects gave no results in this compound,
probably due to the early discovery of this molecule, which did not permit the collection
of enough data.
Considering the predictions for the cytotoxic activity towards cancer cell lines, we
observed two results with Pa values of 0.501 and 0.513 for two breast cancer cell lines,
namely, MDA-MB-231 and MCF7 (Table 13). Because a wide-spectrum of information rel-
ative to belantamab mafodotin is correlated to its biological activity in MM, this prediction
could be useful for in vitro studies to understand the potential mechanisms underpinning
different phenotype-associated breast cancers. We also identified from the DIGEP predic-
tion up-regulated and down-regulated genes following the results of mRNA levels (Table
14). The genes identified are deeply involved in metabolic processes. Interestingly, among
down-regulated genes, we identified ALDH18A1, which is an allelic variant of the alde-
hyde dehydrogenase family. Since previous studies showed that the activity of ALDH1, a
member of ALDH superfamily, was increased in MM stem cells [128], the identification
of its related variant by predictive analysis could be useful for a better understanding of
the role of the mutated forms of related genes involved in not only metabolic dysregula-
tion associated with MM but also with other diseases.

Table 13. Prediction of the possible cancer cell lines sensitive to belantamab mafodotin treatment
for cytotoxic activity.
Cell Line Full Name and Code Tissue Pa Pi
Breast adenocarcinoma MDA-MB-231 Breast 0.501 0.028
Breast carcinoma MCF7 Breast 0.513 0.049

Table 14. DIGEP prediction of belantamab mafotin-regulated genes.

Down-Regulated Up-Regulated
Pa Pi Pa Pi
Genes Genes
ALDH18A1 0.698 0.098
SHC1 0.550 0.040
C10ORF118 0.631 0.063
NSF 0.546 0.117
TMEM41B 0.606 0.051
H6PD 0.524 0.127
AKR1C3 0.511 0.211

With the ShinyGo tool, we predicted the possible GO biological and molecular func-
tions. We applied an FDR cut-off of 0.05 for both biological processes and molecular func-
tions. Data were represented by each category name related to fold enrichment -log10
(FDR). As we can see in Figure 5A, the higher bar size in the biological process is repre-
sented by the category of genes that are involved in regulating the sesquiterpenoid meta-
bolic process and the regulation of the isoprenoid process. On the other hand, one of the
most representative molecular functions was related to phosphotransferase activity (Fig-
ure 5B). Moreover, since we detected breast systems, such as MDA-MB-231 and MCF7, as
possible sensitive cancer cell lines, in vitro study could be deepened to extrapolate
Mar. Drugs 2023, 21, 24 20 of 27

additional information on these cancer-associated signatures even if the clinical benefits

have not been confirmed as in the case of MM.

Figure 5. GO predictive analysis of differentially expressed belantamab-related genes. (A) Biological

processes on queried belantamab-dependent genes. Data show each pathway sorted by category
related to fold enrichment with -log10 (FDR) and applying an FDR cut-off of 0.05. (B) Molecular
function on queried belantamab-dependent genes. Data show each pathway sorted by category re-
lated to fold enrichment with -log10 (FDR) and applying an FDR cut-off of 0.05.

7. Conclusions
Cancer diagnostics and treatments have reached a very high degree of complexity in
recent years, also considering the interaction between the different fields of study, the ap-
proaches used to gather knowledge and the information available for the search for anti-
cancer drug candidates [129]. Subsequently, drugs from increasingly specific natural and
synthetic sources have been developed, making possible the identification of important
biomarkers that are able to improve the appropriacy of therapies [111]. Marine pharma-
cology is a rapidly growing discipline [16] thanks to the integration of biotechnologies
based on marine organisms and the preclinical and clinical applications of produced nat-
ural compounds, such as primary and secondary metabolites. Currently, there are many
drugs on the market with active ingredients of marine origin with various therapeutic
activities including anti-cancer ones [25]. As described on “the marine pharmaceuticals
Mar. Drugs 2023, 21, 24 21 of 27

website” (https://www.marinepharmacology.org/, accessed on 10 October 2022), many

marine compounds are currently in phase 1, 2 and 3 trials, while 17 studies have been
approved by global regulatory authorities for the treatment of a wide range of diseases
[130]. In the first part of this review, we deeply discussed the current literature about the
latest approved anticancer biomolecules of three different kinds of marine organisms. We
introduced the marine sources, the molecule structures and the biological potentialities,
as well as the optimization of the compound for therapeutical efficacy and approval. On
the basis of the previously described information, in the second part of the review, we
selected three molecules from each related organism as a model to offer an overview about
the possible bioinformatic applications for a better understanding of their biological activ-
ity. Thus, we firstly discussed the use of an online software, PASS, to evaluate the general
biological potential of the described drugs. Thanks to simultaneous predictions based on
the structure of the interrogated compounds, we were able to estimate the effectiveness of
molecules also in the pathological contexts different from their current therapeutic use.
Once the drug-related biological activities were predicted, we consulted the PASS-con-
nected service, DIGEP-pred, to predict drug-induced gene expression, and finally, we ex-
amined GO biological and molecular functions with the ShinyGo tool. As for panobino-
stat, many predicted HDAC inhibitory activities were confirmed by the used tools, but
few studies reported its activity as a chemosensitizer or calcium channel activator. Despite
preclinical studies, panobinostat confirmed its biological potentials in MM; this drug was
predicted to be active also in colon, lung and breast cancer cell lines as a single agent and
also in combination with other therapies for solid tumors [39]. Differentially expressed
genes associated with panobinostat were detected, indicating its metabolic role in differ-
ent diseases. Plitidepsin was another analyzed molecule, and it represents a concrete ex-
ample of a re-proposed drug used recently for the treatment of COVID-19 unlike other re-
proposed drugs, such as lopinavir–ritonavir, hydroxychloroquine, remdesivir and inter-
feron beta 1a, which were supposed to be inefficient [131,132]. Consulting the tools, many
broad-spectrum plitidepsin-related biological activities were detected to be in line with
previous findings [55]. Interestingly, among differentially expressed genes regulated by
plitidepsin, TMEM41B was identified as a common target for SARS-CoV-2 infection.
The last molecule interrogated in our tool was belantamab mafodotin, which showed
from predictions immunostimulant and proteasome ATPase inhibitor activities. Bel-
antamab, approved for RRMM, seemed to share interesting previsions about cytotoxic ef-
fects also towards the MDA-MB-231 and MCF7 breast cancer cell lines, suggesting its po-
tential effect also in solid tumors. From the DIGEP predictions, we detected many differ-
entially regulated genes, and among these, we focused our attention on the down-regu-
lated ALDH18A1 gene, which could be a potential alternative target for MM [128].
Some of the predicted activities we found are partly in line with the already present
knowledge thanks to the increase in deposited big data that can help a better characteri-
zation of the clinical–pathological features of treated patients.
The obtained results could be useful for giving new information about already
known and discovered compounds but can also give suggestions about other possible
pharmacological applications or new targets (e.g., the evaluation of different cancer cell
lines that are sensitive to the compound). The predictions of the reported three case stud-
ies represent an example of the application of these tools, which can give additional infor-
mation about already known compounds and also suggest further insights to help follow-
ing studies on new bioactive compounds of marine origin.

Supplementary Materials: The following supporting information can be downloaded at:

https://www.mdpi.com/article/10.3390/md21010024/s1; Table S1: Biological activities of
Psammaplin A and different marine sources; Table S2: Most recent clinically approved anticancer
compounds from marine species; Table S3: List of molecules analyzed by PASS software, presenting
their structural chemical formula, the SMILE format and the Mol file.
Mar. Drugs 2023, 21, 24 22 of 27

Author Contributions: Conceptualization, M.C.; software, G.S. and M.C.; investigation, G.S. and
M.C.; data curation, M.C. and G.S.; writing—original draft preparation, M.C and G.S.; writing—
review and editing, L.A. and A.N.; supervision, M.C. and L.A. All authors have read and agreed to
the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Please add “Informed consent was obtained from all subjects in-
volved in the study.” OR “Patient consent was waived due to REASON (please provide a detailed
justification).” OR “Not applicable” for studies not involving humans.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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