IntroductionLung cancer ranks first in deaths among malignancies and approximately 1.59 million people (19.4% of all cancer deaths excluding nonmelanoma skin cancer) die worldwide from lung cancer every year (Ferlay et al., 2013). The 5-year survival rate for nonsmall-cell lung cancer is estimated to be 10.5% for females and 9.4% for males (Caldarella et al., 2007). No symptoms are detected in the early stage of most lung cancer cases, which results in late diagnosis (Carter-Harris et al., 2014;Shim et al., 2014). Despite the recently developed diagnostic methods, the localization of detected tumors is not limited to the lungs. The most important difficulty in lung cancer therapy is metastasis to different organs or different sites in the lung, which makes it almost impossible to fully eradicate the tumor by surgery, radiotherapy, and chemotherapy. Hence, resistance to chemotherapeutics becomes crucial in patients with no chance of curative surgery.The acidity of the tumor microenvironment is one of the important factors in chemotherapy resistance. The vacuolar (H + )-ATPases (V-ATPases) that pump H + from the cytoplasm to extracellular compartments have a critical role in acidity (Perez-Sayans et al., 2009). These multisubunit V-ATPase complexes are basically expressed in all eukaryotic cells, although there are variations in subunits (Wagner et al., 2004). However, they are preferentially expressed in various cancer types including pancreatic cancer, oral squamous cell cancer, and nonsmall-cell lung carcinoma compared to nonmalignant tissues, and higher expression levels of V-ATPases are linked to malignant phenotypes (Sennoune et al., 2004;Chung et al., 2011;Garcia-Garcia et al., 2012;Qiang et al., 2013). Consequently, therapeutic approaches to inhibit V-ATPases are expected to increase sensitivity towards antineoplastic agents or overcome chemoresistance.Tumor tissues, and especially solid tumors, possess different microenvironmental features (Vaupel, 2004). The