Repurposed cAMP-Modulating Agents Enhance 5-Fluorouracil Response Through Membrane-Dependent Mechanisms

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.