Role of the tumor microenvironment in the activity and expression of the p-glycoprotein in human colon carcinoma cells.
The metabolic microenvironment of solid tumors is characterized by an oxygen deficiency and increased anaerobic glycolysis leading to extracellular acidosis and ATP depletion, which in turn may affect other energy-dependent cellular pathways. Since many tumors overexpress active drug transporters (e.g. the p-glycoprotein) leading to a multidrug-resistant phenotype, this study analyzes the impact of the different aspects of the extracellular microenvironment (hypoxia and acidosis) on the activity and expression of the p-glycoprotein (pGP) in the human colon carcinoma cell line LS513. For up to 24 h cells were exposed to hypoxia (pO2<0.5 mmHg), an acidic extracellular environment (pH 6.6), or the combination of hypoxia and acidosis. Under hypoxic conditions (at a normal pH), the pGP activity (measured by the daunorubicin efflux) and the pGP expression were not markedly altered. Under acidic conditions, however, the pGP-mediated drug efflux was increased, an effect which was even more pronounced when the cells were exposed to hypoxia and acidosis simultaneously (increasing the pGP-activity by 70%). The cellular pGP expression remained almost constant under these conditions, indicating that the increased transport rate results from a functional modulation. The findings of the present study indicate that the parameters of the tumor microenviroment (especially extracellular acidosis) can increase the pGP-mediated drug efflux, an effect which may explain the reduced cytotoxicity of chemotherapeutic agents in hypoxic/acidic tumors.