Many tumors exhibit mechanisms by which chemotherapeutic agents can be actively transported out of the cell, leading to a chemoresistant phenotype. One important member of this ABC-transporter family is the multidrug resistance-related protein 1 (MRP1). On the other hand, solid growing tumors often show pronounced microenvironmental differences as compared to normal tissue, such as hypoxia (due to insufficient perfusion), metabolic acidosis (as a result of forced glycolysis) and ATP depletion. It has previously reported that the activity of the p-glycoprotein (pGP) another member of the ABC-family is strongly affected by the extracellular acidosis leading to increased transport activity and chemoresistance.

Aim of this study was to analyze whether the environmental changes also alter the MRP1-activity and expression.

R3327-AT1 prostate cancer cells were exposed to pronounced hypoxia (pO₂ < 1 mmHg) or extracellular acidosis (pH= 6.6) for up to 24h. The MRP1-activity was measured by the calcein efflux in presence or absence of the MRP1-inhibitor probenecid. The expression was determined by a whole cell ELISA. Extracellular acidosis increased the MRP1-activity during the first 6 h moderately by approx. 40%, where after the activity returned to control values. Since no changes in the MRP1-expression could be detected, the increase in transport rate seems to be the result of a functional improvement. However, the increase in transport rate was much smaller as compared to pGP (+140%). Hypoxia alone without acidosis had no impact neither on the MRP1-transport rate nor the expression.

These results show that besides the p-glycoprotein the activity of the MRP1 is also affected by acidosis however to a much smaller extent. At present it is unclear whether the same signal pathways (p38, ERK1/2) play a role for the alterations of the MRP1.