{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T01:08:21Z","timestamp":1775610501968,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2014,1,16]],"date-time":"2014-01-16T00:00:00Z","timestamp":1389830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>In the course of a screening program for the inhibitors of angiogenesis from marine sources, AD0157, a pyrrolidinedione fungal metabolite, was selected for its angiosupressive properties. AD0157 inhibited the growth of endothelial and tumor cells in culture in the micromolar range. Our results show that subtoxic doses of this compound inhibit certain functions of endothelial cells, namely, differentiation, migration and proteolytic capability. Inhibition of the mentioned essential steps of in vitro angiogenesis is in agreement with the observed antiangiogenic activity, substantiated by using two in vivo angiogenesis models, the chorioallantoic membrane and the zebrafish embryo neovascularization assays, and by the ex vivo mouse aortic ring assay. Our data indicate that AD0157 induces apoptosis in endothelial cells through chromatin condensation, DNA fragmentation, increases in the subG1 peak and caspase activation. The data shown here altogether indicate for the first time that AD0157 displays antiangiogenic effects, both  in vitro and in vivo, that are exerted partly by targeting the Akt signaling pathway in activated endothelial cells. The fact that these effects are carried out at lower concentrations than those required for other inhibitors of angiogenesis makes AD0157 a new promising drug candidate for further evaluation in the treatment of cancer and other  angiogenesis-related pathologies.<\/jats:p>","DOI":"10.3390\/md12010279","type":"journal-article","created":{"date-parts":[[2014,1,16]],"date-time":"2014-01-16T11:14:29Z","timestamp":1389870869000},"page":"279-299","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["The Marine Fungal Metabolite, AD0157, Inhibits Angiogenesis by Targeting the Akt Signaling Pathway"],"prefix":"10.3390","volume":"12","author":[{"given":"Melissa","family":"Garc\u00eda-Caballero","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of M\u00e1laga, Campus de Teatinos, M\u00e1laga 29071, Spain"},{"name":"Unidad 741 de CIBER \"de Enfermedades Raras\", University of M\u00e1laga, M\u00e1laga E-29071, Spain"},{"name":"International Campus of Excellence Andaluc\u00eda Tech, M\u00e1laga 29071, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Librada","family":"Ca\u00f1edo","sequence":"additional","affiliation":[{"name":"Biomar Microbial Technologies, Parque Tecnol\u00f3gico de Le\u00f3n, Parcela M-10.4,  Armunia (Le\u00f3n) 24009, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Fern\u00e1ndez-Medarde","sequence":"additional","affiliation":[{"name":"Biomar Microbial Technologies, Parque Tecnol\u00f3gico de Le\u00f3n, Parcela M-10.4,  Armunia (Le\u00f3n) 24009, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7275-6462","authenticated-orcid":false,"given":"Miguel","family":"Medina","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of M\u00e1laga, Campus de Teatinos, M\u00e1laga 29071, Spain"},{"name":"Unidad 741 de CIBER \"de Enfermedades Raras\", University of M\u00e1laga, M\u00e1laga E-29071, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Quesada","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of M\u00e1laga, Campus de Teatinos, M\u00e1laga 29071, Spain"},{"name":"Unidad 741 de CIBER \"de Enfermedades Raras\", University of M\u00e1laga, M\u00e1laga E-29071, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2014,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1146\/annurev-cellbio-092910-154002","article-title":"Developmental and pathological angiogenesis","volume":"27","author":"Chung","year":"2011","journal-title":"Annu. Rev. Cell. Dev. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/nature04478","article-title":"Angiogenesis in life, disease and medicine","volume":"438","author":"Carmeliet","year":"2005","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3932","DOI":"10.2174\/138161210794454950","article-title":"Do not say ever never more: The ins and outs of antiangiogenic therapies","volume":"1","author":"Quesada","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1002\/med.20059","article-title":"Anti-angiogenic drugs: From bench to clinical trials","volume":"26","author":"Quesada","year":"2006","journal-title":"Med. Res. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.3390\/md8102673","article-title":"Immense essence of excellence: Marine microbial bioactive compounds","volume":"8","author":"Bhatnagar","year":"2010","journal-title":"Mar. Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.biotechadv.2011.03.001","article-title":"Bio-mining the microbial treasures of the ocean: New natural products","volume":"29","author":"Imhoff","year":"2011","journal-title":"Biotechnol. Adv."},{"key":"ref_8","first-page":"261","article-title":"Antiangiogenic activity of aeroplysinin-1, a brominated compound isolated from a marine sponge","volume":"16","author":"Carmona","year":"2002","journal-title":"FASEB J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/ijc.20068","article-title":"Study of puupehenone and related compounds as inhibitors of angiogenesis","volume":"110","author":"Castro","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.3390\/md10092033","article-title":"The antiangiogenic compound aeroplysinin-1 induces apoptosis in endothelial cells by activating the mitochondrial pathway","volume":"10","author":"Medina","year":"2012","journal-title":"Mar. Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1016\/j.bcp.2013.04.007","article-title":"Toluquinol, a marine fungus metabolite, is a new angiosuppresor that interferes with the Akt pathway","volume":"85","author":"Medina","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_12","unstructured":"Fern\u00e1ndez-Medarde, A., Ca\u00f1edo, L., Vinuesa, M.A., S\u00e1nchez-L\u00f3pez, J.M., Calvo, B., Mart\u00ednez-Insua, M., Quesada, A.R., Garc\u00eda-Caballero, M., and Medina, M.A. (2013). Compounds, Their Preparation And Use in Medicaments. (13382284), European Patent Application."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1365-2613.2008.00633.x","article-title":"A critical analysis of current in vitro and in vivo angiogenesis assays","volume":"90","author":"Staton","year":"2009","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1006\/dbio.2002.0711","article-title":"In vivo imaging of embryonic vascular development using transgenic zebrafish","volume":"248","author":"Lawson","year":"2002","journal-title":"Dev. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1387\/ijdb.103222rn","article-title":"Paracrine regulation of angiogenesis by different cell types in the aorta ring model","volume":"55","author":"Nicosia","year":"2011","journal-title":"Int. J. Dev. Biol."},{"key":"ref_16","first-page":"2224","article-title":"Angiogenesis and signal transduction in endothelial cells","volume":"61","author":"Quesada","year":"2004","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.tips.2006.04.006","article-title":"Angiogenesis: From plants to blood vessels","volume":"27","author":"Fan","year":"2006","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.3390\/md8102702","article-title":"Marine Antitumor drugs: Status, shortfalls and strategies","volume":"8","author":"Bhatnagar","year":"2010","journal-title":"Mar. Drugs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"218","DOI":"10.2174\/157489212799972963","article-title":"Anticancer drug discovery from the marine environment","volume":"7","author":"Nastrucci","year":"2012","journal-title":"Recent Pat. Anticancer Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1039\/C005001F","article-title":"Marine natural products","volume":"28","author":"Blunt","year":"2011","journal-title":"Nat. Prod. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"903","DOI":"10.3390\/md11030903","article-title":"Marine-derived angiogenesis inhibitors for cancer therapy","volume":"11","author":"Wang","year":"2013","journal-title":"Mar. Drugs"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3390\/md9020154","article-title":"Antiproliferative and antiangiogenic activities of smenospongine, a marine sponge sesquiterpene aminoquinone","volume":"9","author":"Kong","year":"2011","journal-title":"Mar. Drugs"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.3390\/md11041087","article-title":"6\u2033-Debromohamacanthin A, a Bis (Indole) alkaloid, inhibits angiogenesis by targeting the VEGFR2-mediated PI3K\/AKT\/mTOR signaling pathways","volume":"11","author":"Kim","year":"2013","journal-title":"Mar. Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.ejphar.2005.03.047","article-title":"Hypericin in the dark inhibits key steps of angiogenesis in vitro","volume":"516","author":"Quesada","year":"2005","journal-title":"Eur. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s00394-011-0289-x","article-title":"Anti-angiogenic properties of carnosol and carnosic acid, two major dietary compounds from rosemary","volume":"52","author":"Medina","year":"2013","journal-title":"Eur. J. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1016\/j.bcp.2010.07.006","article-title":"Antiangiogenic effect of licochalcone A","volume":"80","author":"Kim","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1038\/jid.2010.416","article-title":"Dimethylfumarate inhibits angiogenesis in vitro and in vivo: A possible role for its antipsoriatic effect?","volume":"131","author":"Medina","year":"2011","journal-title":"J. Investig. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.foodchem.2012.02.079","article-title":"Evaluation of the anti-angiogenic potential of hydroxytyrosol and tyrosol, two bio-active phenolic compounds of extra virgin olive oil, in endothelial cell cultures","volume":"134","author":"Fortes","year":"2012","journal-title":"Food Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0304-3835(01)00443-8","article-title":"Resveratrol and quercetin inhibit angiogenesis in vitro","volume":"171","author":"Igura","year":"2001","journal-title":"Cancer Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1007\/s00018-006-6399-6","article-title":"Evaluation of the anti-angiogenic effect of aloe-emodin","volume":"63","author":"Quesada","year":"2006","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_31","first-page":"3457","article-title":"A re-evaluation of fumagillin selectivity towards endothelial cells","volume":"21","author":"Medina","year":"2001","journal-title":"Anticancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/S1357-2725(01)00007-3","article-title":"Human endothelial gelatinases and angiogenesis","volume":"33","author":"Nguyen","year":"2001","journal-title":"Int. J. Biochem. Cell. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3884","DOI":"10.1073\/pnas.97.8.3884","article-title":"Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model","volume":"97","author":"Fang","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","first-page":"1048","article-title":"Reduced angiogenesis and tumor progression in gelatinase A-deficient mice","volume":"58","author":"Itoh","year":"1998","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1251\/bpo30","article-title":"Mouse aortic ring assay: A new approach of the molecular genetics of angiogenesis","volume":"4","author":"Masson","year":"2002","journal-title":"Biol. Proced. Online"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.devcel.2008.12.012","article-title":"The Jekyll and Hyde functions of caspases","volume":"16","author":"Yi","year":"2009","journal-title":"Dev. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7482","DOI":"10.1038\/sj.onc.1209088","article-title":"The Akt\/PKB pathway: Molecular target for cancer drug discovery","volume":"24","author":"Cheng","year":"2005","journal-title":"Oncogene"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2174\/156800908783497122","article-title":"AKT signaling in regulating angiogenesis","volume":"8","author":"Jiang","year":"2008","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.bbadis.2009.12.009","article-title":"Pathological roles of MAPK signaling pathways in human diseases","volume":"1802","author":"Kim","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1023\/A:1026028303196","article-title":"Regulation of matrix metalloproteinases: An overview","volume":"253","author":"Chakraborti","year":"2003","journal-title":"Mol. Cell. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1083\/jcb.66.2.451","article-title":"Mitogenic effect of fibroblast growth factor on early passage cultures of human and murine fibroblasts","volume":"66","author":"Gospodarowicz","year":"1975","journal-title":"J. Cell. Biol."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/12\/1\/279\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:07:25Z","timestamp":1760216845000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/12\/1\/279"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,16]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,1]]}},"alternative-id":["md12010279"],"URL":"https:\/\/doi.org\/10.3390\/md12010279","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,1,16]]}}}