The metabolic microenvironment of solid tumors is characterized by oxygen deficiency and obligatory glycolysis which leads to extracellular acidosis and ATP depletion and thus may affect energy-dependent cellular pathways. Since many tumors overexpress the p-glycoprotein (pGP) - leading to a multidrug resistant phenotype - this study attempted to analyze the impact of the extracellular environment (oxygenation, pH) on the activity and expression of pGP in the human colon carcinoma cell-line LS513. Cells were exposed to hypoxia (pO₂<0.5 mmHg), an acidic extracellular environment (pH=6.6), or the combination of both for up to 24 h. Under hypoxic conditions (at normal pH), the pGP-activity (measured by daunorubicin uptake) as well as pGP-expression was not markedly altered. Under acidic conditions however, pGP-mediated drug efflux was increased. This effect was even more pronounced when cells were exposed to combined hypoxia and acidosis. The cellular pGP-expression remained almost constant under these conditions, indicating that the increased transport rate results from a functional modulation of pGP-mediated drug efflux by the tumor microenvironment (in particular through the extracellular acidosis) which may explain the reduced cytotoxicity of some chemotherapeutic agents in hypoxic/acidic tumors.

B.G., M.G.: Institute of Physiology, University of Wuerzburg