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

Area of Science:

• Oncology
• Molecular Pharmacology
• Cancer Cell Biology

Background:

• 5-Fluorouracil (5-FU) is a cornerstone chemotherapy for solid tumors, but its efficacy is limited by chemoresistance and variable patient response.
• While intracellular factors are traditionally implicated, the plasma membrane's role in regulating drug response is increasingly recognized.
• The plasma membrane acts as a critical interface for drug transport, signaling, and cell fate determination.

Purpose of the Study:

• To propose a membrane-centered framework for enhancing 5-FU efficacy by modulating cancer cell membrane properties.
• To investigate the role of compartmentalized cAMP/PKA signaling, influenced by vasoregulatory agents, in overcoming 5-FU resistance.
• To explore the potential of targeting the membrane phenotype for improved cancer therapy and patient stratification.

Main Methods:

• Utilized a framework centered on cAMP/PKA signaling modulation via repurposed vasoregulatory agents (levosimendan, milrinone, terbutaline).
• Investigated the functional remodeling of the cancer cell membrane, including lipid raft organization and transporter (ENT1/SLC29A1) trafficking.
• Examined the impact on drug influx/efflux balance, intracellular 5-FU bioavailability, and downstream signaling pathways (redox, mitochondria, apoptosis).

Main Results:

• cAMP/PKA signaling modulation functionally remodeled the cancer cell membrane, enhancing 5-FU response.
• Membrane remodeling influenced transporter trafficking and drug bioavailability, potentially overcoming pseudo-resistance.
• cAMP-dependent signaling shifted cellular responses towards apoptosis and integrated with known resistance mechanisms.
• Differential sensitivity was observed in bladder versus prostate cancer models, suggesting membrane phenotype biomarkers.

Conclusions:

• The plasma membrane is a dynamic therapeutic interface that can be functionally remodeled to enhance chemotherapy.
• Repurposed vasoregulatory agents can modulate cAMP signaling to improve 5-FU efficacy by targeting membrane properties.
• This membrane-centered approach offers potential for drug repurposing, patient stratification, and personalized combination cancer therapies.