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Brachydin A (BrA), a glycosylated flavonoid extracted from Fridericia platyphylla, displays a remarkable antitumoral effect against in vitro mPCa cells cultured as bidimensional (2D) monolayers. Considering that three-dimensional (3D) cell cultures provide a more accurate response to chemotherapeutic agents, this study investigated the antiproliferative\/antimetastatic effects of BrA and the molecular mechanisms underlying its action in mPCa spheroids (DU145) in vitro. BrA at 60\u2013100 \u03bcM was cytotoxic, altered spheroid morphology\/volume, and suppressed cell migration and tumor invasiveness. High-content analysis revealed that BrA (60\u2013100 \u00b5M) reduced mitochondrial membrane potential and increased apoptosis and necrosis markers, indicating that it triggered cell death mechanisms. Molecular analysis showed that (i) 24-h treatment with BrA (80\u2013100 \u00b5M) increased the protein levels of DNA disruption markers (cleaved-PARP and p-\u03b3-H2AX) as well as decreased the protein levels of anti\/pro-apoptotic (BCL-2, BAD, and RIP3K) and cell survival markers (p-AKT1 and p-44\/42 MAPK); (ii) 72-h treatment with BrA increased the protein levels of effector caspases (CASP3, CASP7, and CASP8) and inflammation markers (NF-kB and TNF-\u03b1). Altogether, our results suggest that PARP-mediated cell death (parthanatos) is a potential mechanism of action. In conclusion, BrA confirms its potential as a candidate drug for preclinical studies against mPCa.<\/jats:p>","DOI":"10.3390\/pharmaceutics14050963","type":"journal-article","created":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T07:08:58Z","timestamp":1651475338000},"page":"963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The Antitumoral\/Antimetastatic Action of the Flavonoid Brachydin A in Metastatic Prostate Tumor Spheroids In Vitro Is Mediated by (Parthanatos) PARP-Related Cell Death"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1715-966X","authenticated-orcid":false,"given":"Diego Luis","family":"Ribeiro","sequence":"first","affiliation":[{"name":"Departament of Genetics, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14049-900, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5624-8019","authenticated-orcid":false,"given":"Katiuska","family":"Tuttis","sequence":"additional","affiliation":[{"name":"Departament of Genetics, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14049-900, Brazil"}]},{"given":"Larissa Cristina Bastos de","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Department of General Biology, Center for Biological Sciences, State University of Londrina, Londrina 86057-970, Brazil"}]},{"given":"Juliana Mara","family":"Serpeloni","sequence":"additional","affiliation":[{"name":"Department of General Biology, Center for Biological Sciences, State University of Londrina, Londrina 86057-970, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0551-138X","authenticated-orcid":false,"given":"Izabela Natalia Faria","family":"Gomes","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3632-343X","authenticated-orcid":false,"given":"Andr\u00e9 van Helvoort","family":"Lengert","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3578-1869","authenticated-orcid":false,"given":"Cl\u00e1udia Quintino da","family":"Rocha","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Center for Exact Sciences and Technology, Federal University of Maranh\u00e3o, S\u00e3o Lu\u00eds 65080-805, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9639-7940","authenticated-orcid":false,"given":"Rui Manuel","family":"Reis","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4806-909 Guimar\u00e3es, Portugal"},{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9098-1698","authenticated-orcid":false,"given":"Ilce Mara de Syllos","family":"C\u00f3lus","sequence":"additional","affiliation":[{"name":"Department of General Biology, Center for Biological Sciences, State University of Londrina, Londrina 86057-970, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3079-4388","authenticated-orcid":false,"given":"Lus\u00e2nia Maria Greggi","family":"Antunes","sequence":"additional","affiliation":[{"name":"Department of Clinical Analysis, Toxicology, and Food Sciences, School of Pharmaceutical Sciences of Ribeir\u00e3o Preto, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14040-903, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.14740\/wjon1191","article-title":"Epidemiology of Prostate Cancer","volume":"10","author":"Rawla","year":"2019","journal-title":"World J. 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