# Personalized Combination Therapy in Bladder Cancer: cAMP Modulators Synergize with 5-FU and Modulate Redox Programs

## TL;DR

This study shows that combining heart and asthma drugs with 5-FU chemotherapy improves bladder cancer treatment by enhancing drug effectiveness and reducing resistance.

## Contribution

The study identifies tumor-specific synergy between cAMP modulators and 5-FU in bladder cancer, offering a novel personalized therapy approach.

## Key findings

- Milrinone and terbutaline synergized with 5-FU to reduce bladder cancer cell viability and migration.
- Terbutaline reduced oxidative stress in bladder cancer cells, potentially limiting treatment resistance.
- The drug combinations were effective only in bladder cancer, not in lung or prostate cancer models.

## Abstract

Bladder cancer patients often show variable responses to chemotherapy, highlighting the need for more personalized treatment strategies. One promising approach is drug repurposing, which explores new anticancer uses for medications already approved for other diseases. In this study, we tested two cardiovascular drugs, milrinone and terbutaline, in combination with the commonly used chemotherapy drug 5-fluorouracil (5-FU). We found that these drugs significantly enhanced the anticancer effects of 5-FU in bladder cancer cells, but not in lung or prostate cancer models, indicating a tumor-specific benefit. Importantly, terbutaline also reduced harmful oxidative stress inside bladder cancer cells, which may help limit treatment resistance. These findings support the idea that selected heart and asthma medications could be repurposed to improve chemotherapy outcomes in bladder cancer when guided by appropriate biomarkers.

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.