It is indeed known that low extracellular pH can trigger several proteases such as MMP-2, MMP-9, cathepsin B, and cathepsin L and result in acidity-induced up-regulation of the proangiogenic factors VEGF-A and IL-8 [25, 26]. As a consequence, the neutralization of these mechanisms has been actively pursued by many investigators who have been only partially successful, since so far it has been possible to block one or more MMPases but not all them simultaneously [27]. A recent publication points out that by inhibiting of V-ATPases through RNA interference, it was possible to prevent cancer metastases in a murine

model [28]. This approach Metformin price offers a new strategy to cope with the process of tumor spread (that is mediated by a continuous process of extracellular matrix degradation and

tumor angiogenesis) by raising the extracellular tumor pH, thus arresting the activation of matrix degradating proteases. Finally, besides being a potential target of anticancer drugs, it is conceivable that V-ATPases might become a predictive factor of tumor behaviour and final outcome through the immunohistochemical evaluation of their expression and cellular distribution in tumor biopsies [29–31]. Role of V-ATPases in chemoresistance The acidic microenvironment caused by changes in the pH gradient between the intracellular and the extracellular compartments as well as the pH gradient between the cytoplasm and the intracellular organelles can be significantly involved in the mechanism of drug resistance [32, 33].

There are several mechanisms involved MDV3100 nmr in this phenomenon, including decreased uptake or neutralization of weakly basic drugs by the acidic tumor microenvironment or the sequestration of chemotherapy drugs within lysosomal vesicles [32–36]. An accelerated turnover of acidic vesicles may represent an additional tumor strategy of drug resistance D-malate dehydrogenase based on counteracting current transportation [37]. Several investigators developed new approaches to better characterize tumor pH in animal models [38, 39] mostly through imaging systems in order to identify novel targets. As a result, new approaches have been developed to modulate drug efficacy within the low pH tumor milieu including the use of RNA interference, bicarbonates or the induction of metabolic alkalosis [40–43]. Finally, two recently published articles describe the chemosensitizing action of proton pump inhibitors (omeprazole) in a murine model of orthotopic cutaneous melanoma, a well known chemo-refractory neoplasm, opening a novel field of investigation [44, 45]. Pump inhibitors as antitumor drugs The various functions played by V-ATPases in tumors, including proliferation, tumorigenesis, drug resistance and tumor progression, make them potential targets for preclinical investigators and clinicians.