Proton Pump Inhibitors in Cancer Treatment Strategies

Proton pump inhibitors (PPIs) have traditionally been employed to reduce gastric acidity, but emerging evidence has repurposed these agents as adjuvants in oncology. Tumour cells often exploit proton pumps—particularly vacuolar H⁺-ATPases—to maintain an acidic extracellular microenvironment that promotes invasion, metastatic dissemination and resistance to cytotoxic therapies. By inhibiting these proton extrusion mechanisms, PPIs can neutralise peritumoural acidity, restore intracellular pH homeostasis and enhance drug uptake. Beyond pH modulation, PPIs have been shown to interact with signalling pathways associated with apoptosis, autophagy and drug efflux, thereby sensitising malignant cells to chemotherapy and potentially improving survival outcomes. Network pharmacology analyses further suggest that PPIs may engage targets implicated in lipid metabolism, growth factor signalling and extracellular matrix remodelling. Taken together, these findings have propelled investigation into PPI-based strategies that span direct tumour cell cytotoxicity, chemosensitisation and optimisation of the tumour microenvironment.

Research from Nature Portfolio

Recent studies have demonstrated that commonly prescribed PPIs can influence the course of breast cancer by modulating both tumour cell physiology and host comorbidities. Large-scale epidemiological analyses indicate that long-term use of certain PPIs is associated with improved overall and disease-free survival in non-metastatic breast cancer, suggesting a beneficial off-target effect on tumour progression. Concurrently, network pharmacology approaches have identified shared molecular targets between PPIs, cancer-associated pathways and metabolic diseases, revealing interactions with key proteins such as AKT1 and MMP9. These investigations highlight the capacity of PPIs to interfere with fatty acid transport, insulin resistance and apoptotic signalling, offering a mechanistic rationale for repurposing these agents in integrated therapeutic regimens.

Proton Pump Inhibitors in Cancer Treatment Strategies publication trend

The graph below shows the total number of articles in proton pump inhibitors in cancer treatment strategies across all publications each year (not limited to Nature Index journals).

Technical terms

Extracellular tumour microenvironment: The local milieu surrounding cancer cells, characterised by pH, nutrient and oxygen gradients that influence tumour behaviour.

Vacuolar H⁺-ATPase (V-ATPase): A proton pump responsible for acidifying intracellular compartments and exporting protons to the extracellular space in tumour cells.

Network pharmacology: An integrative approach that maps drug–target interactions across molecular networks to elucidate polypharmacological effects.

Chemical exchange saturation transfer (CEST) MRI: An imaging modality that detects pH-dependent exchange of protons between water and solute molecules to map tissue acidity non-invasively.

Alkalisation therapy: A treatment approach aimed at raising systemic or local pH, often through dietary interventions and administration of buffering agents.

References

1. Concomitant medication, comorbidity and survival in patients with breast cancer. Nature Communications (2024).
2. Potential of Alkalization Therapy for the Management of Metastatic Pancreatic Cancer: A Retrospective Study. Cancers (2023).
3. Network pharmacology analysis reveals potential targets and mechanisms of proton pump inhibitors in breast cancer with diabetes. Scientific Reports (2023).
4. Assessing the Therapeutic Efficacy of Proton Transport Inhibitors in a Triple-Negative Breast Cancer Murine Model with Magnetic Resonance Imaging—Chemical Exchange Saturation Transfer Tumor pH Imaging. Metabolites (2023).