Abstract
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.
Keywords: Proton pump inhibitors, omeprazole, cancer therapy, tumor pH, V-ATPase, cell survival, aerobic glycolysis, cellular pH homeostasis, cytotoxic drugs, hypoxia
Current Pharmaceutical Design
Title: A Rationale for the Use of Proton Pump Inhibitors as Antineoplastic Agents
Volume: 18 Issue: 10
Author(s): Angelo De Milito, Maria Lucia Marino and Stefano Fais
Affiliation:
Keywords: Proton pump inhibitors, omeprazole, cancer therapy, tumor pH, V-ATPase, cell survival, aerobic glycolysis, cellular pH homeostasis, cytotoxic drugs, hypoxia
Abstract: 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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Cite this article as:
De Milito Angelo, Lucia Marino Maria and Fais Stefano, A Rationale for the Use of Proton Pump Inhibitors as Antineoplastic Agents, Current Pharmaceutical Design 2012; 18 (10) . https://dx.doi.org/10.2174/138161212799504911
DOI https://dx.doi.org/10.2174/138161212799504911 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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