Tumors often show pronounced extracellular acidosis (pHe) which results from glycolytic metabolism under hypoxic but also under normoxic conditions. The intracellular pH is much less affected due to efficient cellular H+-transport. In a broad spectrum of cells it was demonstrated that extracellular acidosis led to phosphorylation of the mitogen-activated-protein-kinases (MAPK) ERK1/2 and p38. ERK1/2 activation was seen only with extracellular acidosis whereas p38 phosphorylation was also elicited by sole intracellular lactacidosis at normal pHe. No evidence for the involvement of the kinases c-SRC, PKC, PKA, PI3K or EGFR nor changes in cell volume in acidosis-induced MAPK activation was obtained. However, acidosis induced the formation of reactive oxygen species (ROS), probably originating from mitochondria, which then activated p38. ROS scavenging prevented MAPK activation.

Phosphorylation of these MAPK led to a rapid functional activation of the drug transporting p-glycoprotein (Pgp) which is responsible for a chemoresistant phenotype of tumors. As a consequence tumor cells in an acidic environment showed reduced chemosensitivity. These effects were confirmed in vivo by forcing tumor acidosis which also led to p38 activation and increased chemoresistance. Measuring Pgp transport activitiy in vivo using PET imaging clearly demonstrated that tumor acidosis significantly stimulated the Pgp activity. Here, p38-MAPK pathway played an important role, whereas ERK1/2 was of minor importance. Other possible consequences of acidosis-induced MAPK-activation might be changes in gene expression and other functional properties of tumor cells.

From these results new strategies for overcoming multidrug resistance (e.g., reducing tumor acidosis, inhibition of p38) may be developed.