{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T03:14:30Z","timestamp":1775445270307,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"crossref","award":["2023\/02032-9"],"award-info":[{"award-number":["2023\/02032-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004263","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio Grande do Sul","doi-asserted-by":"crossref","award":["19\/2551-0001767-7"],"award-info":[{"award-number":["19\/2551-0001767-7"]}],"id":[{"id":"10.13039\/501100004263","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"crossref","award":["310438\/2020-9"],"award-info":[{"award-number":["310438\/2020-9"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: The development of effective oncologic therapies with fewer adverse effects is often limited by the intrinsic and acquired resistance of tumor cells. Hybrid molecules, rationally designed to combine different pharmacophores, represent a promising strategy by providing synergistic effects, dose reduction, and a lower risk of resistance. In this study, the antitumor potential and mechanisms of action of 22 novel hybrid compounds derived from xanthene and pyran scaffolds (SJ022\u2013SJ103) were investigated. The hybrids were initially evaluated through in vitro screening in four breast, three ovarian, and two prostate cancer cell lines, followed by the selection of T-47D, OVCAR-3, and LNCaP cells for detailed assays assessing cytotoxicity, apoptosis, cell cycle distribution, DNA damage, caspase-3\/7 activity, morphology, and PI3K\/AKT\/mTOR pathway modulation. Methods: Cytotoxicity assays were performed in the selected cell lines, while mechanistic studies included apoptosis and cell cycle analysis by flow cytometry, \u03b3H2AX detection, Western blotting for PI3K\/AKT\/mTOR pathway proteins, and 3D spheroid assays. Combinatorial effects with hormone therapies (tamoxifen, fulvestrant, and letrozole) and the AKT inhibitor MK2206 were evaluated. AKT silencing by esiRNA and molecular docking was performed to confirm target engagement. Results: SJ028 demonstrated broad activity across all tested cell lines, whereas SJ064 and SJ078 exhibited higher selectivity. Treatments induced apoptosis, S\/G2-M arrest, and DNA damage, accompanied by decreased phospho-AKT levels and stable PI3K and mTOR expression. In 3D models, the hybrids increased caspase-3\/7 activity and necrotic core expansion. Co-administration with hormone therapies resulted in synergistic effects in breast and ovarian cancer cells, reducing IC50 values by more than 50% in both parental and resistant models, while combinations with MK2206 were antagonistic across all tumor subtypes. AKT silencing abrogated cytotoxicity, and docking confirmed SJ028 binding to AKT. Conclusions: Xanthene- and pyran-based hybrids\u2014particularly SJ028, SJ064, and SJ078\u2014showed strong antitumor activity through apoptosis induction, cell cycle arrest, and PI3K\/AKT pathway modulation. Their preserved efficacy in resistant models and synergistic interactions with hormone therapies contrasted with the antagonism observed with AKT inhibition, highlighting their potential as promising candidates for the treatment of hormone-responsive and -resistant cancers.<\/jats:p>","DOI":"10.3390\/pharmaceutics17111470","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T10:07:03Z","timestamp":1763114823000},"page":"1470","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hybrid Dihydropyrimidinones Targeting AKT Signaling: Antitumor Activity in Hormone-Dependent 2D and 3D Cancer Models"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5494-0894","authenticated-orcid":false,"given":"Amanda Helena","family":"Tejada","sequence":"first","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos 14784-400, SP, Brazil"}]},{"given":"Samuel Jos\u00e9","family":"Santos","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00ednteses Org\u00e2nicas, Instituto de Qu\u00edmica, Universidade Federal do Rio Grande do Sul, Porto Alegre 90010-150, RS, Brazil"}]},{"given":"Gabriel Tofolli","family":"Lobo","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos 14784-400, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1535-4819","authenticated-orcid":false,"given":"Abu-Bakr Adetayo","family":"Ariwoola","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos 14784-400, SP, Brazil"}]},{"given":"Aryel Jos\u00e9 Alves","family":"Bezerra","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos 14784-400, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5217-7823","authenticated-orcid":false,"given":"Giulia Rodrigues","family":"Stringhetta","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos 14784-400, SP, 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, Antenor Duarte Villela, 1331, Barretos 14784-400, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7470-4655","authenticated-orcid":false,"given":"Luciane Sussuchi","family":"da Silva","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos 14784-400, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9639-7940","authenticated-orcid":false,"given":"Rui Manuel V.","family":"Reis","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos 14784-400, SP, Brazil"},{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4704-553 Braga, Portugal"},{"name":"ICVS\/3B\u2019s-PT Government Associate Laboratory, 4710-057 Braga\/4806-909 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6561-7322","authenticated-orcid":false,"given":"Daniel D\u2019Almeida","family":"Preto","sequence":"additional","affiliation":[{"name":"Clinical Oncology Department, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos 14784-400, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5968-9760","authenticated-orcid":false,"given":"Dennis","family":"Russowsky","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de S\u00ednteses Org\u00e2nicas, Instituto de Qu\u00edmica, Universidade Federal do Rio Grande do Sul, Porto Alegre 90010-150, RS, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6500-4190","authenticated-orcid":false,"given":"Renato Jos\u00e9","family":"Silva-Oliveira","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Antenor Duarte Villela, 1331, Barretos 14784-400, SP, Brazil"},{"name":"Faculty of Health Sciences of Barretos Dr. Paulo Prata\u2013FACISB, Barretos 14785-002, SP, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"ref_1","first-page":"17","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. 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