{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T23:14:02Z","timestamp":1790896442788,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PNRA (the Italian National Antarctic Research Program)","award":["PNRA18_00005-D"],"award-info":[{"award-number":["PNRA18_00005-D"]}]},{"name":"PNRA (the Italian National Antarctic Research Program)","award":["PRSA 20-21"],"award-info":[{"award-number":["PRSA 20-21"]}]},{"name":"Ministry of Education, University and Research (MIUR)","award":["PNRA18_00005-D"],"award-info":[{"award-number":["PNRA18_00005-D"]}]},{"name":"Ministry of Education, University and Research (MIUR)","award":["PRSA 20-21"],"award-info":[{"award-number":["PRSA 20-21"]}]},{"name":"Department of Biology, University of Tor Vergata","award":["PNRA18_00005-D"],"award-info":[{"award-number":["PNRA18_00005-D"]}]},{"name":"Department of Biology, University of Tor Vergata","award":["PRSA 20-21"],"award-info":[{"award-number":["PRSA 20-21"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cancer remains a leading cause of death worldwide, highlighting the urgent need for novel and more effective treatments. Natural products, with their structural diversity, represent a valuable source for the discovery of anticancer compounds. In this study, we screened 750 Antarctic extracts to identify potential inhibitors of human topoisomerase 1 (hTOP1), a key enzyme in DNA replication and repair, and a target of cancer therapies. Bioassay-guided fractionation led to the identification of palmitic acid (PA) as the active compound from the Antarctic sponge Artemisina plumosa, selectively inhibiting hTOP1. Our results demonstrate that PA irreversibly blocks hTOP1-mediated DNA relaxation and specifically inhibits the DNA religation step of the enzyme\u2019s catalytic cycle. Unlike other fatty acids, PA exhibited unique specificity, which we confirmed through comparisons with linoleic acid. Molecular dynamics simulations and binding assays further suggest that PA interacts with hTOP1-DNA complexes, enhancing the inhibitory effect in the presence of camptothecin (CPT). These findings identify PA as a hTOP1 inhibitor with potential therapeutic implications, offering a distinct mechanism of action that could complement existing cancer therapies.<\/jats:p>","DOI":"10.3390\/ijms26052018","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T04:46:37Z","timestamp":1740545197000},"page":"2018","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Unveiling the Mechanism of Action of Palmitic Acid, a Human Topoisomerase 1B Inhibitor from the Antarctic Sponge Artemisina plumosa"],"prefix":"10.3390","volume":"26","author":[{"given":"Alessio","family":"Ottaviani","sequence":"first","affiliation":[{"name":"Department of Onco-Hematology, Gene and Cell Therapy, Bambino Ges\u00f9 Children\u2019s Hospital-IRCCS, Via Ferdinando Baldelli 38, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5154-6154","authenticated-orcid":false,"given":"Davide","family":"Pietrafesa","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bini Chhetri","family":"Soren","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagadish Babu","family":"Dasari","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4621-6291","authenticated-orcid":false,"given":"Stine S. H.","family":"Olsen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of South Florida, USF Sweetgum Ln 12111, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Messina","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Demofonti","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Chicarella","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0505-8645","authenticated-orcid":false,"given":"Keli","family":"Agama","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Convent Drive 37, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Pommier","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Convent Drive 37, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5491-1131","authenticated-orcid":false,"given":"Blasco","family":"Morozzo della Rocca","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7511-6575","authenticated-orcid":false,"given":"Federico","family":"Iacovelli","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6162-6814","authenticated-orcid":false,"given":"Alice","family":"Romeo","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3990-4758","authenticated-orcid":false,"given":"Mattia","family":"Falconi","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3033-5779","authenticated-orcid":false,"given":"Bill J.","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of South Florida, USF Sweetgum Ln 12111, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Fiorani","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy"},{"name":"Institute of Translational Pharmacology, National Research Council, CNR, Via del Fosso del Cavaliere 100, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"McKie, S.J., Neuman, K.C., and Maxwell, A. 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