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Growing evidence has demonstrated that the extracts of different holothurian species exert beneficial effects on human health. Triple negative breast cancers (TNBC) are highly malignant tumors that present a poor prognosis due to the lack of effective targeted therapies. In the attempt to identify novel compounds that might counteract TNBC cell growth, we studied the effect of the exposure of the TNBC cell line MDA-MB231 to total and filtered aqueous extracts of the coelomic fluid obtained from the sea cucumber Holoturia tubulosa, a widespread species in the Mediterranean Sea. In particular, we examined cell viability and proliferative behaviour, cell cycle distribution, apoptosis, autophagy, and mitochondrial metabolic/cell redox state. The results obtained indicate that both total and fractionated extracts are potent inhibitors of TNBC cell viability and growth, acting through both an impairment of cell cycle progression and mitochondrial transmembrane potential and a stimulation of cellular autophagy, as demonstrated by the increase of the acidic vesicular organelles and of the intracellular protein markers beclin-1, and total LC3 and LC3-II upon early exposure to the preparations. Identification of the water-soluble bioactive component(s) present in the extract merit further investigation aiming to develop novel prevention and/or treatment agents efficacious against highly metastatic breast carcinomas.

We examined the effects of the ferrocene-based histone deacetylase-3 inhibitor Pojamide (N1-(2-aminophenyl)-N8-ferrocenyloctanediamide) and its two derivatives N1-(2-aminophenyl)-N6-ferrocenyladipamide and N1-(2-aminophenyl)-N8-ferroceniumoctanediamide tetrafluoroborate on triple-negative MDA-MB-231 breast cancer cells. Viability/growth assays indicated that only the first two compounds at 70 μM concentration caused an approximate halving of cell number after 24 h of exposure, whereas the tetrafluoroborate derivative exerted no effect on cell survival nor proliferation. Flow cytometric and protein blot analyses were performed on cells exposed to both Pojamide and the ferrocenyladipamide derivative to evaluate cell cycle distribution, apoptosis/autophagy modulation, and mitochondrial metabolic state in order to assess the cellular basis of the cytotoxic effect. The data obtained show that the cytotoxic effect of the two deacetylase inhibitors may be ascribed to the onset of non-apoptotic cell death conceivably linked to a down-regulation of autophagic processes and an impairment of mitochondrial function with an increase in intracellular reactive oxygen species. Our work expands the list of autophagy-regulating drugs and also provides a further example of the role played by the inhibition of autophagy in breast cancer cell death. Moreover, the compounds studied may represent attractive and promising targets for subsequent molecular modeling for anti-neoplastic agents in malignant breast cancer.

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 ...

Human parathyroid hormone‐related protein (PTHrP) is a polyhormone that undergoes proteolytic cleavage producing smaller peptides which exert diversified biological effects. PTHrP signalization is prominently involved in breast development and physiology, but the studies have been focused onto either N‐terminal species or full‐length protein introduced by gene transfer techniques. Our present work investigates for the first time the effect of the mid‐region PTHrP secretory form, that is, the fragment [38–94], on HB2 non‐tumoral breast epithelial cells. We examined viability/proliferation of cells grown in PTHrP‐containing media supplemented with different serum concentration and on different substrates, extending our investigation to check whether (a) by analogy with MDA‐MB231 cells, also HB2 cell chromatin possesses genome‐wide binding sites for mid‐region PTHrP, and (b) the peptide is endowed with modulating properties toward the expression of proliferation/differentiation signatures by HB2 cells. Our results indicate that mid‐region PTHrP acts as a cell growth/differentiation stimulator in routine and “nutrient stress” culture conditions, accordingly reprogramming gene expression, and is able to bind to cytogenetic preparations from HB2 cells. This supports the concept that the physiological mechanisms involving PTHrP during breast development may include mature processed forms of the protein different from the N‐terminal fragment. © 2018 BioFactors, 45(2):279–288, 2019