New Cytotoxic Cerebrosides from the Red Sea Cucumber Holothuria spinifera Supported by In-Silico Studies

Abstract

Bioactivity-guided fractionation of a methanolic extract of the Red Sea cucumber Holothuria spinifera and LC-HRESIMS-assisted dereplication resulted in the isolation of four compounds, three new cerebrosides, spiniferosides A (1), B (2), and C (3), and cholesterol sulfate (4). The chemical structures of the isolated compounds were established on the basis of their 1D NMR and HRMS spectral data. Metabolic profiling of the H. spinifera extract indicated the presence of diverse secondary metabolites, mostly hydroxy fatty acids, diterpenes, triterpenes, and cerebrosides. The isolated compounds were tested for their in vitro cytotoxicities against the breast adenocarcinoma MCF-7 cell line. Compounds 1, 2, 3, and 4 displayed promising cytotoxic activities against MCF-7 cells, with IC50 values of 13.83, 8.13, 8.27, and 35.56 µM, respectively, compared to that of the standard drug doxorubicin (IC50 8.64 µM). Additionally, docking studies were performed for compounds 1, 2, 3, and 4 to elucidate their binding interactions with the active site of the SET protein, an inhibitor of protein phosphatase 2A (PP2A), which could explain their cytotoxic activity. This study highlights the important role of these metabolites in the defense mechanism of the sea cucumber against fouling organisms and the potential uses of these active molecules in the design of new anticancer agents.

Holospiniferoside: A New Antitumor Cerebroside from The Red Sea Cucumber Holothuria spinifera: In Vitro and In Silico Studies

“…The cytotoxicity and the antiapoptotic effects of ceramides and cerebrosides against a wide array of cancer cell lines have been reported in several studies [ 12 , 33 , 34 , 35 ]. In addition, the crude extract of H. spinifera has been reported to possess potent cytotoxic potential against MCF7 with an IC 50 value of 4.58 µg/mL [ 12 ].…”

“…The cytotoxicity and the antiapoptotic effects of ceramides and cerebrosides against a wide array of cancer cell lines have been reported in several studies [ 12 , 33 , 34 , 35 ]. In addition, the crude extract of H. spinifera has been reported to possess potent cytotoxic potential against MCF7 with an IC 50 value of 4.58 µg/mL [ 12 ]. Therefore, the cytotoxicity of the new cerebroside (compound 1) was assessed on breast cancer cell line (MCF-7) by the sulforhodamine B (SRB) assay using the method described in [ 12 , 36 , 37 ].…”

“…In addition, the crude extract of H. spinifera has been reported to possess potent cytotoxic potential against MCF7 with an IC 50 value of 4.58 µg/mL [ 12 ]. Therefore, the cytotoxicity of the new cerebroside (compound 1) was assessed on breast cancer cell line (MCF-7) by the sulforhodamine B (SRB) assay using the method described in [ 12 , 36 , 37 ]. The color intensity was measured, and the IC 50 values were then calculated using an ELISA reader.…”

“…The organic extracts of the sea cucumber species ( Holothuria leucospilota and Holothuria scabra ) exert antiproliferative action on human C33A cervical cancer cells and A549 nonsmall lung cancer cells [ 8 ]. In addition, Holothuria spinifera extract possess anticancer properties against the breast cancer cell line (MCF-7) [ 12 ]. Moreover, Holothuria leucospilota have antimicrobial and antileishmanial effects [ 13 , 14 ].…”

“…These compounds have been reported to possess anticancer, antiangiogenic, antimicrobial, anti-inflammatory, and immunomodulatory properties [ 7 ]. It is worth noting that we have previously reported the isolation of new cytotoxic cerebrosides [ 12 ]. Hence, the present study aims to pursue our phytochemical investigation of Holothuria spinifera , assess the antitumor effect of the newly isolated compounds against the breast cancer (MCF-7) cell line, and predict the possible mechanism of action by the aid of molecular-docking approaches.…”