Associação Portuguesa de Investigação em Cancro
Repurposing Positive Inotropic Agents as a Potential Strategy for Personalized Treatment of Bladder Cancer
Repurposing Positive Inotropic Agents as a Potential Strategy for Personalized Treatment of Bladder Cancer
Authors and Affiliations: Eduarda Ribeiro 1,2 and Nuno Vale 1,3,4,*
1 PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; up202211879@edu.icbas.up.pt
2 School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
3 RISE-Health, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
4 Laboratory of Personalized Medicine, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
Abstract:
Background/Objectives: Repurposed cAMP-elevating agents may personalize fluoropyrimidine therapy by exploiting pathway-specific vulnerabilities. Methods: We tested the PDE3 inhibitor milrinone and the β2-agonist terbutaline alone or combined with 10 µM 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–Talalay/CompuSyn. Results: In UM-UC-5, both agents reduced viability, migration, and clonogenicity and synergized with 5-FU (CI < 1 across Fa ≈0.42–0.57). 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., β2-AR/PDE3/PI3K–Akt features) for personalized therapy in bladder cancer; mechanistic and in vivo validation are warranted.
Journal: Cancers
