{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T12:46:53Z","timestamp":1770814013572,"version":"3.50.1"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020 Operational Program for Competitiveness and International-ization"},{"name":"Portuguese funds through Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004"]}]},{"name":"Portuguese funds through Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["PRR-09\/C06-834I07\/2024.P11721"],"award-info":[{"award-number":["PRR-09\/C06-834I07\/2024.P11721"]}]},{"name":"Portuguese funds through Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["2024.18026.PEX"],"award-info":[{"award-number":["2024.18026.PEX"]}]},{"name":"CHAIR in Onco-Innovation from the Faculty of Medicine, University of Porto"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Repurposed cAMP-elevating agents may personalize fluoropyrimidine therapy by exploiting pathway-specific vulnerabilities. Methods: We tested the PDE3 inhibitor milrinone and the \u03b22-agonist terbutaline alone or combined with 10 \u03bcM 5-fluorouracil (5-FU) in UM-UC-5 (bladder), A549 (lung), and PC-3 (prostate) cells. Viability, migration, clonogenicity, and intracellular ROS (DCFDA) were measured; drug interactions used Chou\u2013Talalay\/CompuSyn. Results: In UM-UC-5, both agents reduced viability, migration, and clonogenicity and synergized with 5-FU (CI &lt; 1 across Fa \u2248 0.42\u20130.57). 5-FU increased ROS, whereas terbutaline consistently lowered ROS below baseline and blunted 5-FU-induced oxidative signals; milrinone showed a dose-dependent redox profile without consistent ROS suppression. A549 combinations did not outperform 5-FU; PC-3 was largely unresponsive. Conclusions: cAMP modulators selectively potentiate 5-FU in bladder cancer cells and modulate redox programs (notably with terbutaline), supporting a biomarker-guided combination strategy (e.g., \u03b22-AR\/PDE3\/PI3K\u2013Akt features) for personalized therapy in bladder cancer; mechanistic and in vivo validation are warranted.<\/jats:p>","DOI":"10.3390\/cancers18040562","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T12:42:42Z","timestamp":1770640962000},"page":"562","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Personalized Combination Therapy in Bladder Cancer: cAMP Modulators Synergize with 5-FU and Modulate Redox Programs"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5370-9586","authenticated-orcid":false,"given":"Eduarda","family":"Ribeiro","sequence":"first","affiliation":[{"name":"PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"Laboratory of Personalized Medicine, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"ref_1","first-page":"85","article-title":"Global burden of cancer","volume":"79","author":"Ma","year":"2006","journal-title":"Yale J. 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