Cell-Free Coelomic Fluid Extracts of the Sea Urchin Arbacia lixula Impair Mitochondrial Potential and Cell Cycle Distribution and Stimulate Reactive Oxygen Species Production and Autophagic Activity in Triple-Negative MDA-MB231 Breast Cancer Cells

Abstract

Triple-negative breast cancer (TNBC) is a highly malignant tumor histotype which lacks effective targeted therapies, thereby being considered as the most aggressive form of breast carcinoma. To identify novel compounds which could counteract TNBC cell growth, we explored the in vitro effects of crude extracts and <10 kDa-filtered fractions of the coelomic fluid obtained from the sea urchin Arbacia lixula on TNBC MDA-MB231 cells. We examined cell viability, cycle distribution, apoptotic/autophagic activity, and mitochondrial polarization/cell redox status. Here, we report the first data demonstrating an anti-TNBC effect by A. lixula-derived coelomic fluid extracts. Thus, identification of the water-soluble bioactive component(s) contained in the extracts deserve(s) further investigation aimed to devise novel promising prevention and/or treatment agents effective against highly malignant breast tumors.Further studies conducted by Björn et al. [8] demonstrated that the synthetic peptides sequentially derived from the previously characterized centrocin 1 (CEN1 HC-Br and CEN1 HC) showed prominent microbicidal and anti-inflammatory activities on in vivo and in vitro mammalian models, representing an interesting resource for the treatment of infections in humans.Furthermore, a recent study by Katelnikova et al. [9] highlighted that a glycopeptide fraction (GPF) derived from internal organs of the green sea urchins Strongylocentrotus droebachiensis possesses relevant anti-inflammatory effects, especially for the treatment of bronchitis. Moreover, the absorption and pharmacokinetics of GPF following single and repeated intranasal administration were evaluated over the course of seven days in rats [10].Another echinoderm species from which bioactive molecules were studied is Arbacia lixula, commonly found in the Mediterranean Sea and in the African Atlantic coast [11]. So far, the biomedical applications of molecules extracted from this marine invertebrate are very limited. Of note, Stabili et al. [12] demonstrated the powerful antioxidant effect exerted by the lysate of A. lixula's coelomocytes, the immune cells present in the coelomic fluid (CF) of the sea urchin, whereas Cirino et al. [13] highlighted that A. lixula's eggs are a rich source of astaxanthin, a radical scavenger that can prevent neurodegenerative diseases. These promising findings prompted an extension of the study on the pharmacological potential of A. lixula-derived substances, whose massive sourcing represents an easy task due to the abundance of this marine species in waters surrounding Sicily, also being a thermophilic species which is expanding very quickly due to the increase of the surface temperature of the Mediterranean Sea [14].Triple-negative breast cancers (TNBC) are categorized among the highly "aggressive" malignant carcinomas. In fact, the lack of expression of estrogen, progesterone, and epidermal growth factor type 2 (HER2) receptors makes them poorly responsive to hormonal therapies and to HER2-targeting drugs, and the TNBC histotype ...

Marine Animal-Derived Compounds and Autophagy Modulation in Breast Cancer Cells

“…A specimen of the A. lixula sea urchin. Taken from [75].…”

“…Both organisms have been widely used as models to examine the effects of anthropogenic chemical and noise pollution [78][79][80]. On the basis of the acknowledged diverse biological and pharmacological properties shown by the compounds and extracts from sea urchins and holothurians [82][83][84][85], in search of novel potential anti-breast cancer preparations, crude and <10 kDa-filtered fractions of cell-free aqueous extracts of the coelomic fluids from A. lixula and H. tubulosa were administered to MDA-MB231 TNBC cells, and the biological aspects of the observed cytotoxic effects were investigated [75,81].…”

“…Of note, autophagy upregulation occurred in parallel with ROS overproduction and the blocking of the cell cycle at the S-phase with no evidence of dissipation of the mitochondrial transmembrane potential and the onset of apoptosis. The obtained results allowed for the speculation that (1) the increase of the endogenous ROS levels could be a consequence of cellular metabolic stress and impairment of the antioxidant system in the absence of mitochondrial potential dysfunction; (2) autophagy upregulation could be a result of intracellular signalization switched on by ROS, acting as redox signaling molecules; and (3) autophagy might be responsible for the blocking of the cell cycle at the S-phase, analogous with the data pro- On the basis of the acknowledged diverse biological and pharmacological properties shown by the compounds and extracts from sea urchins and holothurians [82][83][84][85], in search of novel potential anti-breast cancer preparations, crude and <10 kDa-filtered fractions of cell-free aqueous extracts of the coelomic fluids from A. lixula and H. tubulosa were administered to MDA-MB231 TNBC cells, and the biological aspects of the observed cytotoxic effects were investigated [75,81].…”

Collective Locomotion of Human Cells, Wound Healing and Their Control by Extracts and Isolated Compounds from Marine Invertebrates

“…The phylum Echinodermata, gathering invertebrates that display a radial symmetry, incorporates about 6000 living marine species around the globe. In recent years, echinoderms have attracted much attention as producers of biomolecules with promising anti-microbial, anti-protozoal, anti-fungal, and anticancer properties, making them potential candidates for drug development and future therapeutic applications [165][166][167][168]. Astropecten indicus (Döderlein, 1888; Asteroidea, Paxillosida: Astropectinidae; Figure 23), also called comb star or sand star, is a starfish that is distributed in the tropical environments of the Indo-Pacific area, and in particular of the United Arab Emirates, Qatar, Thailand, Gulf of Mannar, and Palk Bay region.…”

Histone Deacetylase Inhibitors from Marine Invertebrates

“…These products contribute to the adaptation mechanisms to the specific life conditions in the greatly different marine ecosystems [26]. A large proportion of invertebrate-derived extracts and isolated compounds has shown active pharmacological properties, such as anticancer, antimicrobial, and anti-inflammatory, among others, with an extensive spectrum of biomedical applications that makes them already approved or prospective drugs of marine origin with promising results for different therapeutic purposes [27][28][29][30][31][32]. Within this scenario, the aim of this review is to gather selected studies that reported the extraction and identification of marine invertebrate-derived chemicals that possess HDACi properties and recapitulate the molecular, biochemical, and/or physiological aspects, where available, which are associated with the examined molecules.…”