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

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Fluoropyrimidine chemotherapy, including 5-fluorouracil (5-FU), is a cornerstone in cancer treatment.
• Personalizing 5-FU therapy by targeting specific cellular vulnerabilities is an active area of research.
• Cyclic adenosine monophosphate (cAMP)-elevating agents are being explored for repurposing in cancer therapy.

Purpose of the Study:

• To investigate the potential of repurposed cAMP-elevating agents, milrinone and terbutaline, to enhance 5-FU efficacy.
• To evaluate the effects of these combinations on cancer cell viability, migration, and clonogenicity.
• To explore the modulation of intracellular reactive oxygen species (ROS) by these agents and their impact on 5-FU response.

Main Methods:

• Testing milrinone (PDE3 inhibitor) and terbutaline (β2-agonist) alone and with 5-FU in bladder (UM-UC-5), lung (A549), and prostate (PC-3) cancer cell lines.
• Assessing cell viability, migration, and clonogenicity.
• Measuring intracellular ROS levels and analyzing drug interactions using Chou-Talalay/CompuSyn methods.

Main Results:

• Milrinone and terbutaline synergized with 5-FU in UM-UC-5 bladder cancer cells, reducing viability, migration, and clonogenicity.
• Terbutaline significantly lowered ROS, blunting 5-FU-induced oxidative stress, while milrinone had a variable redox effect.
• A549 and PC-3 cells showed limited or no response to the combination therapies.

Conclusions:

• cAMP modulators selectively potentiate 5-FU in bladder cancer cells, highlighting a potential for personalized therapy.
• The modulation of redox programs, particularly by terbutaline, is a key mechanism in this potentiation.
• Biomarker-guided combination strategies targeting pathways like β2-AR, PDE3, and PI3K-Akt warrant further investigation and in vivo validation for bladder cancer treatment.