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Approved Anticancer Compounds from Marine Sponges: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Mariarosaria Conte.

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. To date, more than 5300 natural compounds have been isolated from sponges or their associated bacteria, and this number is constantly updating.

  • cancer
  • marine environment
  • bioinformatic tools
  • anticancer compounds

1. Introduction

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][1]. To date, more than 5300 natural compounds have been isolated from sponges or their associated bacteria, and this number is constantly updating [15][2]. 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 production of secondary metabolites is an important strategy to react to all these conditions, and many of these bioactive compounds can be exploited for human needs [16][3].
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][4].

2. Eribulin Mesylate

Eribulin mesylate (E7389, Halaven®, Eisai Inc., under license from Eisai R&D Management Co., Ltd. © 2022 Eisai Inc. HALA-US3824; Cambridge, MA, USA, us.eisai.com, accessed on 23 October 2022) 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][5]. 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 limited its use [20][6]. 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 cancer (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 advanced MBC after two prior anthracycline- and taxane-based regimens [21][7].
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][8]. 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. TResearchis study ers confirmed the outcomes observed in the clinical trials, maintaining expected clinical activity and respecting a tolerable safety profile [23][9]. Eribulin elicits anticancer activity via mitotic and non-mitotic mechanisms of action. It prevents the formation 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][10]. 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][11]. The resulting studies also showed a different response in the tissues treated with eribulin compared to classical microtubulin-targeting agents; in particular, different effects on peripheral nerves, angiogenesis, vascular remodeling and epithelial-to-mesenchymal transition were detected, affecting differently the tumor microenvironment [26][12].

3. Panobinostat

Panobinostat (LBH-589, Farydak®, Novartis Pharmaceuticals Corporation East Hanover, 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 revised with the current name Pseudoceratina purpurea [27][13]. 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 activities (Supplementary Table S1) [28,29,30,31,32,33] [14][15][16][17][18][19]. 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][20] and psammaplyn E–J [35,36][21][22]. The synthetic production of these compounds intensified the research on their potentialities and applications while also considering 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-negative breast cancer, endometrial and prostate cancers [37[23][24][25],38,39], as well as on multiple myeloma (MM) cells [40][26]. 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 differentiation. Panobinostat plays an important role in epigenetic regulation involving histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities [35,39][21][25]. 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 transcriptional 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][27][28]. These cumulative effects lead to the inhibition of cellular proliferation and cell-cycle arrest or apoptosis in malignant cells [43][29]. Another important action of panobinostat in cancer cells is the inhibition of aminopeptidase N, which is involved in different processes, such as proliferation, angiogenesis and tumor invasion [31,44][17][30]. 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 clinical 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][31] (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][7]47,[8][10][12][32][33][34]
Panobinostat Hydroxamic acid derivative Sponge Pseudoceratina purpurea HDAC inhibitor [40,43,45,49,50,51][26][29][31][35][36][37]
Aminopeptidase-N inhibitor [44][30]
DNA Methyltransferase inhibitor [35][21]

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