{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:59:30Z","timestamp":1790060370593,"version":"4.0.1"},"reference-count":52,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:00:00Z","timestamp":1656374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>The natural environment represents an important source of drugs that originates from the terrestrial and, in minority, marine organisms. Indeed, the marine environment represents a largely untapped source in the process of drug discovery. Among all marine organisms, sponges with algae represent the richest source of compounds showing anticancer activity. In this study, the two secondary metabolites pelorol (PEL) and 5-epi-ilimaquinone (EPI), purified from Dactylospongia elegans were investigated for their anti-melanoma activity. PEL and EPI induced cell growth repression of 501Mel melanoma cells in a concentration- and time-dependent manner. A cell cycle block in the G1 phase by PEL and EPI was also observed. Furthermore, PEL and EPI induced significant accumulation of DNA histone fragments in the cytoplasmic fraction, indicating a pro-apoptotic effect of both compounds. At the molecular level, PEL and EPI induced apoptosis through the increase in pro-apoptotic BAX expression, confirmed by the decrease in its silencing miR-214-3p and the decrease in the anti-apoptotic BCL-2, MCL1, and BIRC-5 mRNA expression, attested by the increase in their silencing miRNAs, i.e., miR-193a-3p and miR-16-5p. In conclusion, our data indicate that PEL and EPI exert cytotoxicity activity against 501Mel melanoma cells promoting apoptotic signaling and inducing changes in miRNA expression and their downstream effectors. For these reasons could represent promising lead compounds in the anti-melanoma drug research.<\/jats:p>","DOI":"10.3390\/md20070427","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T01:48:38Z","timestamp":1656467318000},"page":"427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pro-Apoptotic Activity of the Marine Sponge Dactylospongia elegans Metabolites Pelorol and 5-epi-Ilimaquinone on Human 501Mel Melanoma Cells"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3291-9009","authenticated-orcid":false,"given":"Sara","family":"Carpi","sequence":"first","affiliation":[{"name":"NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, 56126 Pisa, Italy"},{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2753-8487","authenticated-orcid":false,"given":"Egeria","family":"Scoditti","sequence":"additional","affiliation":[{"name":"National Research Council (CNR), Institute of Clinical Physiology (IFC), 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2664-6091","authenticated-orcid":false,"given":"Beatrice","family":"Polini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"},{"name":"Department of Pathology, University of Pisa, Via Savi 10, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9375-6242","authenticated-orcid":false,"given":"Simone","family":"Brogi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"},{"name":"Interdepartmental Center of Marine Pharmacology (<i>MArinePHARMA<\/i>), University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Calderone","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"},{"name":"Interdepartmental Center of Marine Pharmacology (<i>MArinePHARMA<\/i>), University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Proksch","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University D\u00fcsseldorf, Universt\u00e4tsstrasse 1, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2753-0031","authenticated-orcid":false,"given":"Sherif S.","family":"Ebada","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Nieri","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, 56126 Pisa, Italy"},{"name":"Interdepartmental Center of Marine Pharmacology (<i>MArinePHARMA<\/i>), University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Thomford, N.E., Senthebane, D.A., Rowe, A., Munro, D., Seele, P., Maroyi, A., and Dzobo, K. (2018). Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061578"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural products in drug discovery: Advances and opportunities","volume":"20","author":"Atanasov","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural Products as Sources of New Drugs over the Nearly Four Decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"646","DOI":"10.2533\/chimia.2017.646","article-title":"Drugs from the Oceans: Marine Natural Products as Leads for Drug Discovery","volume":"71","author":"Altmann","year":"2017","journal-title":"Chimia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ercolano, G., De Cicco, P., and Ianaro, A. (2019). New Drugs from the Sea: Pro-Apoptotic Activity of Sponges and Algae Derived Compounds. Mar. Drugs, 17.","DOI":"10.3390\/md17010031"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Di Cesare Mannelli, L., Palma Esposito, F., Sangiovanni, E., Pagano, E., Mannucci, C., Polini, B., Ghelardini, C., Dell\u2019Agli, M., Izzo, A.A., and Calapai, G. (2021). Pharmacological Activities of Extracts and Compounds Isolated from Mediterranean Sponge Sources. Pharmaceuticals, 14.","DOI":"10.3390\/ph14121329"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cappello, E., and Nieri, P. (2021). From Life in the Sea to the Clinic: The Marine Drugs Approved and under Clinical Trial. Life, 11.","DOI":"10.3390\/life11121390"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/bjd.15510","article-title":"The global burden of melanoma: Results from the Global Burden of Disease Study 2015","volume":"177","author":"Karimkhani","year":"2017","journal-title":"Br. J. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nrclinonc.2017.43","article-title":"Targeted agents and immunotherapies: Optimizing outcomes in melanoma","volume":"14","author":"Luke","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2147\/ITT.S134842","article-title":"Melanoma treatment in review","volume":"7","author":"Domingues","year":"2018","journal-title":"Immunotargets Ther."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Carpi, S., Polini, B., Poli, G., Alcantara Barata, G., Fogli, S., Romanini, A., Tuccinardi, T., Guella, G., Frontini, F.P., and Nieri, P. (2018). Anticancer Activity of Euplotin C, Isolated from the Marine Ciliate Euplotes crassus, Against Human Melanoma Cells. Mar. Drugs, 16.","DOI":"10.3390\/md16050166"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1023\/A:1020694425356","article-title":"A randomized phase II study of two schedules of bryostatin-1 (NSC339555) in patients with advanced malignant melanoma: A National Cancer Institute of Canada Clinical Trials Group study","volume":"20","author":"Tozer","year":"2002","journal-title":"Investig. New Drugs"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1021\/np900160g","article-title":"Mansouramycins A-D, cytotoxic isoquinolinequinones from a marine streptomycete","volume":"72","author":"Hawas","year":"2009","journal-title":"J. Nat. Prod."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1021\/np000079l","article-title":"Sesquiterpene quinols\/quinones from the Micronesian sponge Petrosaspongia metachromia","volume":"63","author":"Kwak","year":"2000","journal-title":"J. Nat. Prod."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1021\/np990502u","article-title":"Pelorol from the tropical marine sponge Dactylospongia elegans","volume":"63","author":"Goclik","year":"2000","journal-title":"J. Nat. Prod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1182\/blood-2007-03-079699","article-title":"Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells","volume":"110","author":"Ong","year":"2007","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1021\/ol047316m","article-title":"Synthesis of pelorol and analogues: Activators of the inositol 5-phosphatase SHIP","volume":"7","author":"Yang","year":"2005","journal-title":"Org. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6773","DOI":"10.1039\/C8OB01580E","article-title":"Unusual anti-inflammatory meroterpenoids from the marine sponge Dactylospongia sp.","volume":"16","author":"Li","year":"2018","journal-title":"Org. Biomol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Luo, Y., Chen, H., Weng, J., and Lu, G. (2016). Synthesis of Pelorol and Its Analogs and Their Inhibitory Effects on Phosphatidylinositol 3-Kinase. Mar. Drugs, 14.","DOI":"10.3390\/md14060118"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.phytol.2017.09.026","article-title":"Cytotoxic drimane meroterpenoids from the Indonesian marine sponge Dactylospongia elegans","volume":"22","author":"Ebada","year":"2017","journal-title":"Phytochem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1515\/znc-2018-0025","article-title":"Antimalarial activity of the isolates from the marine sponge Hyrtios erectus against the chloroquine-resistant Dd2 strain of Plasmodium falciparum","volume":"73","author":"Ju","year":"2018","journal-title":"Z. Naturforsch. C J. Biosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1021\/np100669p","article-title":"Sesquiterpene benzoxazoles and sesquiterpene quinones from the marine sponge Dactylospongia elegans","volume":"74","author":"Ovenden","year":"2011","journal-title":"J. Nat. Prod."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1021\/np9605302","article-title":"New sesquiterpene hydroquinones from a Taiwanese marine sponge Polyfibrospongia australis","volume":"60","author":"Shen","year":"1997","journal-title":"J. Nat. Prod."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1007\/BF02118428","article-title":"Isometachromin, a new cytotoxic sesquiterpenoid from a deepwater sponge of the family Spongiidae","volume":"48","author":"McConnell","year":"1992","journal-title":"Experientia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"115279","DOI":"10.1016\/j.bmc.2019.115279","article-title":"Targeting the DNA damage response (DDR) by natural compounds","volume":"28","author":"Proksch","year":"2020","journal-title":"Bioorganic Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1242\/jcs.00735","article-title":"Phosphorylation of serine 10 in histone H3, what for","volume":"116","author":"Prigent","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1074\/jbc.M609151200","article-title":"How tyrosine 15 phosphorylation inhibits the activity of cyclin-dependent kinase 2-cyclin A","volume":"282","author":"Welburn","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yan, H., Xu, T., Zhao, H., Lee, K.-C., Wang, H.-Y., and Zhang, Y. (2013). Isoflurane increases neuronal cell death vulnerability by downregulating miR-214. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055276"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1007\/s10495-013-0841-7","article-title":"Ionizing radiation-inducible microRNA miR-193a-3p induces apoptosis by directly targeting Mcl-1","volume":"18","author":"Kwon","year":"2013","journal-title":"Apoptosis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1038\/nm.1880","article-title":"The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities","volume":"14","author":"Bonci","year":"2008","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.3892\/or.2013.2262","article-title":"microRNA-16 represses colorectal cancer cell growth in vitro by regulating the p53\/survivin signaling pathway","volume":"29","author":"Ma","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1097\/CAD.0000000000000246","article-title":"AM251 induces apoptosis and G2\/M cell cycle arrest in A375 human melanoma cells","volume":"26","author":"Carpi","year":"2015","journal-title":"Anticancer Drugs"},{"key":"ref_34","unstructured":"(2022, February 24). NCCN Guidelines Version 3.22 Melanoma Cutaneous. Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/cutaneous_melanoma.pdf."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41419-017-0059-7","article-title":"Cell death-based treatments of melanoma: Conventional treatments and new therapeutic strategies","volume":"9","author":"Mattia","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_36","first-page":"1391","article-title":"Apoptosis, p53, and tumor cell sensitivity to anticancer agents","volume":"59","author":"Brown","year":"1999","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Aranda, M., P\u00e9rez-Ruiz, E., and Redondo, M. (2018). Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123950"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13578-020-00521-0","article-title":"BIRC3 and BIRC5: Multi-faceted inhibitors in cancer","volume":"11","author":"Frazzi","year":"2021","journal-title":"Cell Biosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ejphar.2006.10.061","article-title":"Ilimaquinone, a marine sponge metabolite, displays anticancer activity via GADD153-mediated pathway","volume":"556","author":"Lu","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3389\/fendo.2018.00402","article-title":"Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation","volume":"9","author":"Hayder","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s12935-015-0185-1","article-title":"MicroRNA (miRNA) in cancer","volume":"15","author":"Reddy","year":"2015","journal-title":"Cancer Cell Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nrd.2016.246","article-title":"MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases","volume":"16","author":"Rupaimoole","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1111\/jphp.13351","article-title":"Recent trends in targeting miRNAs for cancer therapy","volume":"72","author":"Shahm","year":"2020","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.3892\/ijmm.2015.2123","article-title":"microRNA-214 enhances the invasion ability of breast cancer cells by targeting p53","volume":"35","author":"Wang","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Duan, Q., Wang, X., Gong, W., Chen, C., He, X., Chen, F., Yang, L., Wan, P., and Wang, D.W. (2012). ER stress negatively modulates the expression of the miR-199a\/214 cluster to regulates tumor survival and progression in human hepatocellular cancer. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031518"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1038\/emboj.2011.102","article-title":"microRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C","volume":"30","author":"Penna","year":"2011","journal-title":"EMBO J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1007\/s12253-011-9406-7","article-title":"Down-regulated miRNA-214 induces a cell cycle G1 arrest in gastric cancer cells by up-regulating the PTEN protein","volume":"17","author":"Xiong","year":"2011","journal-title":"Pathol. Oncol. Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Polini, B., Carpi, S., Doccini, S., Citi, V., Martelli, A., Feola, S., Santorelli, F.M., Cerullo, V., Romanini, A., and Nieri, P. (2020). Tumor Suppressor Role of hsa-miR-193a-3p and -5p in Cutaneous Melanoma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176183"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4903","DOI":"10.1158\/1078-0432.CCR-14-2566","article-title":"A miRNA-Based Signature Detected in Primary Melanoma Tissue Predicts Development of Brain Metastasis","volume":"21","author":"Hanniford","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.3390\/md12052771","article-title":"Actinomycetes from Red Sea Sponges: Sources for Chemical and Phylogenetic Diversity","volume":"12","author":"Abdelmohsen","year":"2014","journal-title":"Mar. Drugs"},{"key":"ref_51","first-page":"110","article-title":"Bioactive compounds from histological extracts of the marine sponge collected from Red Sea as a potential source for medical applications","volume":"17","author":"Hefny","year":"2020","journal-title":"Biosci. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4987","DOI":"10.1002\/anie.201611617","article-title":"Cyanobacterial ent-Sterol-Like Natural Products from a Deviated Ubiquinone Pathway","volume":"56","author":"Moosmann","year":"2017","journal-title":"Angew. Chem. Int. Ed. Engl."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/20\/7\/427\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:55Z","timestamp":1760139595000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/20\/7\/427"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,28]]},"references-count":52,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["md20070427"],"URL":"https:\/\/doi.org\/10.3390\/md20070427","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,28]]}}}