Repurposed cAMP-Modulating Agents Enhance 5-Fluorouracil Response Through Membrane-Dependent Mechanisms.
Ribeiro Eduarda E, Vale Nuno N
Despite its established role as a cornerstone of chemotherapy for solid tumors, 5-Fluorouracil (5-FU) clinical efficacy remains limited by chemoresistance and heterogeneous drug response. Traditional explanations have focused on intracellular metabolism and genetic determinants; however, increasing evidence identifies the plasma membrane as a critical regulatory interface controlling drug availability, signaling integration, and cell fate. Here, we propose a membrane-centered framework in which compartmentalized cAMP/PKA signaling, modulated by repurposed vasoregulatory agents-levosimendan, milrinone, and terbutaline-enhances 5-FU response by functionally remodeling the cancer cell membrane. This remodeling may influence lipid raft organization, ENT1/SLC29A1 transporter trafficking, and the balance between drug influx and efflux, increasing intracellular 5-FU bioavailability and overcoming membrane-mediated pseudo-resistance. In parallel, cAMP-dependent signaling may modulate redox homeostasis, mitochondria-associated membranes, and apoptotic threshold regulation, shifting the cellular response toward irreversible cell death. Importantly, this framework is reconciled with canonical resistance mechanisms-including TYMS upregulation, DPD overexpression, and MMR deficiency-positioning membrane phenotype as a functionally upstream regulatory layer. Differential sensitivity observed experimentally in bladder versus prostate cancer models supports the concept of integrated membrane phenotype biomarkers. Clinical translation requires rigorous pharmacokinetic-pharmacodynamic validation and cardiovascular safety assessment. Redefining the plasma membrane as a dynamic therapeutic interface may provide a rationale for drug repurposing, patient stratification, and personalized combination strategies.