For GW-572016 purchase example, it was described that proton pump inhibitors can induce apoptosis or inhibit tumour cell growth in gastric or hepatoblastoma cancer cell lines but not in non-tumourous primary cells at high concentrations [27,28]. Oral administration of a small molecule inhibitor of V-ATPase, NiK-12192, was reported to cause a significant inhibition of formation of spontaneous metastases of a human lung tumours in nude mice [31]. Furthermore, several studies reported that V-ATPases are involved in tumour invasion and multi-drug-resistance in many types of cancer [16–22]. In addition, a number of authors demonstrated

an effect of PPIs or other V-ATPase inhibitors on cancer treatment. For example, PPIs were shown to increase the sensitivity of colon adenocarcinoma derived cells towards chemotherapeutic drugs [32], or specific inhibitors of V-ATPase were demonstrated to impair the preferential accumulation of daunomycin in lysosomes and to reverse the resistance towards anthracyclines

in drug-resistant HER2 inhibitor renal epithelial cells [33]. In a screening study of small molecules that disturbed the anti-apoptotic function of Bcl-2 or Bcl-xL, Sasazawa and coworkers found that V-ATPase inhibitors such as bafilomycin A1 were able to induce apoptosis in drug resistant cells following treatment with taxol [34]. Further evidence for the role of V-ATPases in chemoresistance was reported from targeted molecular studies: small interfering RNA against the ATP6L subunit of proton pump V-ATPase was shown to attenuate chemoresistance of breast cancer cells [16] and hepatocellular Meloxicam carcinoma xenografts [20]. Regarding the effect of PPI treatment on intra- and extracellular pH, our data are somewhat contradictory to most Sapanisertib concentration reports in the current literature. Tumours were reported to present an intracellular pH ranging from 7.12 to

7.56 (pHi of normal cells: 6.99-7.20), and an extracellular pH of 6.2-6.9 (pHe of normal extracel- lular space: 7.3-7.4), which is controlled by key pH regulators that maintain a neutral/alkaline intracellular pH by eliminating lactate or protons. Extracellular acidity in tumours tends to be associated with a poorer prognosis based on its effect on aggressiveness, metastasis and resistance towards chemotherapy and radiotherapy treatment [35]. Proton pumps such as V-H ATPases play a key role in the control of the intra-extracellular pH-gradient. These pumps are ATP-dependent membrane-based transporters that control pHi and pHe by actively transport protons from the cytoplasmic compartment to the extracellular space or into other intracellular vesicles [36].