{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:40:37Z","timestamp":1760150437298,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T00:00:00Z","timestamp":1701820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"FCT\/MCTES","doi-asserted-by":"publisher","award":["UID\/QUI\/50006\/2020","UIDB\/04423\/2020","UIDP\/04423\/2020"],"award-info":[{"award-number":["UID\/QUI\/50006\/2020","UIDB\/04423\/2020","UIDP\/04423\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Group of Marine Natural Products and Medicinal Chemistry, CIIMAR","award":["UID\/QUI\/50006\/2020","UIDB\/04423\/2020","UIDP\/04423\/2020"],"award-info":[{"award-number":["UID\/QUI\/50006\/2020","UIDB\/04423\/2020","UIDP\/04423\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Dysregulation of the DNA damage response may contribute to the sensitization of cancer cells to DNA-targeting agents by impelling cell death. In fact, the inhibition of the DNA repair pathway is considered a promising anticancer therapeutic strategy, particularly in combination with standard-of-care agents. The xanthonoside XGAc was previously described as a potent inhibitor of cancer cell growth. Herein, we explored its antitumor activity against triple-negative breast cancer (TNBC), ovarian cancer and pancreatic ductal adenocarcinoma (PDAC) cells as a single agent and in combination with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib. We demonstrated that XGAc inhibited the growth of TNBC, ovarian and PDAC cells by inducing cell cycle arrest and apoptosis. XGAc also induced genotoxicity, inhibiting the expression of DNA repair proteins particularly involved in homologous recombination, including BRCA1, BRCA2 and RAD51. Moreover, it displayed potent synergistic effects with olaparib in TNBC, ovarian cancer and PDAC cells. Importantly, this growth inhibitory activity of XGAc was further reinforced in a TNBC spheroid model and in patient-derived ovarian cancer cells. Also, drug-resistant cancer cells showed no cross-resistance to XGAc. Additionally, the ability of XGAc to prevent cancer cell migration was evidenced in TNBC, ovarian cancer and PDAC cells. Altogether, these results highlight the great potential of acetylated xanthonosides such as XGAc as promising anticancer agents against hard-to-treat cancers.<\/jats:p>","DOI":"10.3390\/cancers15245718","type":"journal-article","created":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T03:48:41Z","timestamp":1701834521000},"page":"5718","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5895-6951","authenticated-orcid":false,"given":"Juliana","family":"Calheiros","sequence":"first","affiliation":[{"name":"LAQV\/REQUIMTE, Laborat\u00f3rio de Microbiologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia da Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9003-2601","authenticated-orcid":false,"given":"Liliana","family":"Raimundo","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laborat\u00f3rio de Microbiologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia da Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6190-6282","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Morais","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laborat\u00f3rio de Microbiologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia da Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5330-1005","authenticated-orcid":false,"given":"Ana Catarina","family":"Matos","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laborat\u00f3rio de Microbiologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia da Universidade do Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2588-6058","authenticated-orcid":false,"given":"Sonia Anna","family":"Minuzzo","sequence":"additional","affiliation":[{"name":"Department of Surgery Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy"}]},{"given":"Stefano","family":"Indraccolo","sequence":"additional","affiliation":[{"name":"Department of Surgery Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy"},{"name":"Veneto Institute of Oncology IOV\u2014IRCCS, 35128 Padova, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-4672","authenticated-orcid":false,"given":"Em\u00edlia","family":"Sousa","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia da Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"CIIMAR\u2014Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leix\u00f4es, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4150-8532","authenticated-orcid":false,"given":"Marta Correia da","family":"Silva","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Qu\u00edmica Org\u00e2nica e Farmac\u00eautica, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia da Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"CIIMAR\u2014Centro Interdisciplinar de Investiga\u00e7\u00e3o Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leix\u00f4es, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9531-4939","authenticated-orcid":false,"given":"Luc\u00edlia","family":"Saraiva","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laborat\u00f3rio de Microbiologia, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia da Universidade do Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"880643","DOI":"10.3389\/fonc.2022.880643","article-title":"Homologous Recombination Deficiency in Ovarian, Breast, Colorectal, Pancreatic, Non-Small Cell Lung and Prostate Cancers, and the Mechanisms of Resistance to PARP Inhibitors","volume":"12","author":"Mekonnen","year":"2022","journal-title":"Front. 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