Journal
CURRENT PHARMACEUTICAL DESIGN
Volume 18, Issue 10, Pages 1395-1406Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/138161212799504911
Keywords
Proton pump inhibitors; omeprazole; cancer therapy; tumor pH; V-ATPase
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Funding
- Italian Ministry of Health
- Italian Alliance against Cancer (ACC)
- Italian Association for Cancer Research (AIRC) [5940]
- European Community
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It is becoming increasingly acknowledged that tumorigenesis is not simply characterized by the accumulation of rapidly proliferating, genetically mutated cells. Microenvironmental biophysical factors like hypoxia and acidity dramatically condition cancer cells and act as selective forces for malignant cells, adapting through metabolic reprogramming towards aerobic glycolysis. Avoiding intracellular accumulation of lactic acid and protons, otherwise detrimental to cell survival is crucial for malignant cells to maintain cellular pH homeostasis. As a consequence of the upregulated expression and/or function of several pH-regulating systems, cancer cells display an alkaline intracellular pH (pHi) and an acidic extracellular pH (pHe). Among the pH-regulating proteins, proton pumps play an important role in both drug-resistance and metastatic spread, thus representing a suitable therapeutic target. Proton pump inhibitors (PPI) have been reported as cytotoxic drugs active against several human tumor cells and preclinical data have prompted the investigation of PPI as anticancer agents in humans. This review will update the current knowledge on the antitumor activities of PPI and their potential applications.
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