{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:28:07Z","timestamp":1785414487746,"version":"3.56.0"},"reference-count":48,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T00:00:00Z","timestamp":1780790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009771","name":"American Society of Pharmacognosy","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009771","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/05nyeaz86","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008335","name":"Arizona Biomedical Research Commission","doi-asserted-by":"publisher","award":["RFGA2024-022-023"],"award-info":[{"award-number":["RFGA2024-022-023"]}],"id":[{"id":"10.13039\/100008335","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["IRG-18-161-40"],"award-info":[{"award-number":["IRG-18-161-40"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"award":["IRG-18-161-40"],"award-info":[{"award-number":["IRG-18-161-40"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with few therapeutic options. Topoisomerase II\u03b1 (TOPO2\u03b1) is frequently overexpressed in PDAC and is associated with poor clinical outcomes, yet current TOPO2\u03b1-directed therapies are constrained by limited efficacy and toxicity. Barettin, a brominated indole-containing diketopiperazine isolated from the marine sponge Geodia barretti, has not previously been evaluated against PDAC-relevant targets. Here, we identify barettin as a TOPO2\u03b1 inhibitor using an integrated phenotypic, computational, and biochemical approach. Barettin exerts a cytostatic, non-toxic effect, selectively suppressing proliferation in a subset of PDAC models while showing reduced activity in others, revealing context-dependent efficacy and biological selectivity. Consistent with this, barettin inhibits TOPO2\u03b1-mediated DNA decatenation in vitro, demonstrating direct interference with enzyme activity. These findings support barettin as a selective inhibitor of a cancer-relevant proliferative pathway, uncovering a potential vulnerability in a subset of PDAC.<\/jats:p>","DOI":"10.3390\/md24060201","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T02:32:46Z","timestamp":1780885966000},"page":"201","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Barettin Suppresses Pancreatic Ductal Adenocarcinoma Proliferation via Topoisomerase II\u03b1 Inhibition"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1110-7125","authenticated-orcid":false,"given":"Caleb A.","family":"Seekins","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique R.","family":"Archuleta","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandria E.","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, College of Science, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Podgorski","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8705-0080","authenticated-orcid":false,"given":"Jerry E.","family":"Carr","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6654-6220","authenticated-orcid":false,"given":"Vishal","family":"Kaleeswaran","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, College of Science, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7406-5004","authenticated-orcid":false,"given":"Kayla B.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew E.","family":"Flowers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Hulme","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, College of Science, University of Arizona, Tucson, AZ 85724, USA"},{"name":"Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd W.","family":"Vanderah","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA"},{"name":"Comprehensive Center for Pain and Addiction, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4045-6718","authenticated-orcid":false,"given":"Paco","family":"C\u00e1rdenas","sequence":"additional","affiliation":[{"name":"Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, 752 37 Uppsala, Sweden"},{"name":"Museum of Evolution, Uppsala University, 752 37 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Streicher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA"},{"name":"Comprehensive Center for Pain and Addiction, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3730-0774","authenticated-orcid":false,"given":"Nam Y.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA"},{"name":"Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8722-9187","authenticated-orcid":false,"given":"Christopher","family":"Cartmell","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA"},{"name":"Comprehensive Center for Pain and Addiction, University of Arizona, Tucson, AZ 85724, USA"},{"name":"Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA"},{"name":"Center for Applied Nano Bioscience and Medicine, College of Medicine, University of Arizona, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9694","DOI":"10.3748\/wjg.v22.i44.9694","article-title":"Epidemiology of pancreatic cancer","volume":"22","author":"Ilic","year":"2016","journal-title":"World J. 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