The Impact of Extracellular Low pH on the Anti-Tumor Efficacy Against Mesothelioma

Inflammation and tumors have been demonstrated to have several common characteristics in their microenvironments. Extracellular acidosis is frequently associated both with inflammation area and tumor growth. Measurements of pH in peripheral tissues during the development of inflammation have shown extracellular pH values as low as 5.5–7.0 while the pH values of normal tissues are usually maintained at pH 7.4-7.5 mainly via pulmonary respiration and kidney perfusion of protons (Edlow & Sheldon, 1971). Similary, the extracellular pH in the central regions of tumors decreases below 6.7 in several tumors as a consequence of lactate accumulation derived from a lack of sufficient vascularization or an increase in tumor specific glycolysis under aerobic conditions combined with impaired mitochondrial oxidative phosphorylation (Simmen, 1993; Vaupel, 1989; Warburg, 1956). These pH declines affect cellular or tissue functions because their features are determined mainly by a variety of enzymatic proteins, and all enzymatic activities have each optimal pH. We have previously reported that the low pH conditions alter signal transductions. (1) The phosphorylations of several proteins were upregulated at low pH in leukemia cells (Fukamachi et al., 2001; Hirara et al., 2008). (2) CTIB, an Ikappa B beta variant, regulates cellular survival and gene expression exclusively under acidic environments in Chinese Hamster Ovary cells (Lao et al., 2005, 2006). Furthermore, the gene expressions related with tumor malignancy were upregulated at low pH in several tumor cell lines (Rofstad et al., 2006). These different characteristics dependent on extracellular pH provided us with a perspective that the inhibitory effect of anti-tumor drugs or molecular targeted inhibitors would vary at tumor-specific low pH, and the development of anti-tumor medicines, which have medical properties especially in acidic conditions, would lead to curative therapies for cancers.