Reaproveitamento de fármacos inotrópicos positivos no possível tratamento personalizado do cancro da bexiga

Reaproveitamento de fármacos inotrópicos positivos no possível tratamento personalizado do cancro da bexiga
Este trabalho, recentemente publicado na revista “Cancers”, explorou o potencial de reaproveitamento de dois fármacos moduladores de AMP cíclico (cAMP) — a milrinona (um inibidor da PDE3) e a terbutalina (um agonista β2​) — em combinação com o fármaco de referência 5-fluorouracilo (5-FU). O estudo demonstrou que estes agentes potenciam de forma seletiva a eficácia do 5-FU em células de cancro da bexiga, reduzindo significativamente a sua viabilidade, capacidade migratória e potencial de sobrevivência a longo prazo. A investigação revelou ainda que a terbutalina foi capaz de suprimir o stress oxidativo induzido pela quimioterapia, sugerindo um papel protetor na modulação dos programas redox das células tumorais. Estes resultados reforçam a viabilidade de estratégias terapêuticas personalizadas, visando melhorar a eficácia clínica e reduzir a toxicidade no tratamento do carcinoma urotelial.

Autores e afiliações: 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; [email protected]

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.

Revista: Cancers

Link: https://www.mdpi.com/2072-6694/18/4/562

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