title: Role of the tumor microenvironment in the activity and expression of the p-glycoprotein in human colon carcinoma cells.
abstract: 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.
authors.affiliation: Institute of Physiology and Pathophysiology, University of Mainz, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lotz
authors.forename: Debra K
authors.initials: DK
authors.lastname: Kelleher
authors.forename: Birgit
authors.initials: B
authors.lastname: Gassner
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
authors.forename: Peter
authors.initials: P
authors.lastname: Vaupel
authors.forename: Oliver
authors.initials: O
authors.lastname: Thews
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism*; D000138:Acidosis / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D003630:Daunorubicin / Q000493:pharmacokinetics; D006801:Humans; D006863:Hydrogen-Ion Concentration
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003630:Daunorubicin