Microenvironment acidity as a major determinant of tumor chemoresistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach.
Despite the major progresses in biomedical research and the development of novel therapeutics and treatment strategies, cancer is still among the dominant causes of death worldwide. One of the crucial challenges in the clinical management of cancer is primary (intrinsic) and secondary (acquired) resistance to both conventional and targeted chemotherapeutics. Multiple mechanisms have been identifiedthat underlie intrinsic and acquired chemoresistance: these include impaired drug uptake, increased drug efflux, deletion of receptors, altered drug metabolism, quantitative and qualitative alterations in drug targets, increased DNA damage repair and various mechanisms of anti-apoptosis. The fast efflux of anticancer drugs mediated by multidrug efflux pumps and the partial or complete reversibility of chemoresistance combined with the absence of genetic mutations suggests a multifactorial process. However, a growing body of recent evidence suggests that chemoresistance is often triggered by the highly acidic microenvironment of tumors. The vast majority of drugs, including conventional chemotherapeutics and more recent biological agents, are weak bases that are quickly protonated and neutralized in acidic environments, such as the extracellular microenvironment and the acidic organelles of tumor cells. It is therefore essential to develop new strategies to overcome the entrapment and neutralization of weak base drugs. One such strategy is the use of proton pump inhibitors which can enhance tumor chemosensitivity by increasing the pH of the tumor microenvironment. Recent clinical trials in animals with spontaneous tumors have indicated that patient alkalization is capable of reversing acquired chemoresistance in a large percentage of tumors that are refractory to chemotherapy. Of particular interest was the benefit of alkalization for patients undergoing metronomic regimens which are becoming more widely used in veterinary medicine. Overall, these results provide substantial new evidence that altering the acidic tumor microenvironment is an effective, well tolerated and low cost strategy for the overcoming of anticancer drug resistance.
School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, Nottingham LE12 5RD, UK.
Sophie
S
Taylor
SAFU, Regina Elena Cancer Institute, Via delle Messi d' Oro 156, Rome, Italy.
Enrico Pierluigi
EP
Spugnini
The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
Yehuda G
YG
Assaraf
Department of Therapeutic Research and Medicines Evaluation, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy.
Tommaso
T
Azzarito
School of Veterinary Medicine and Science, University of Nottingham, College Road, Sutton Bonington, Nottingham LE12 5RD, UK. Electronic address: Cyril.Rauch@nottingham.ac.uk.
Cyril
C
Rauch
Department of Therapeutic Research and Medicines Evaluation, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy. Electronic address: stefano.fais@iss.it.
Stefano
S
Fais
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054328:Proton Pump Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000187:drug effects*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; D054328:Proton Pump Inhibitors
Chemotherapy; Intrinsic cancer resistance; Pets; Proton pump inhibitors; Tumor acidity