Effect of efflux pumps expression and cell bioenergetics in the multidrug resistance phenotype in cancer cells

The P-glycoprotein (Pgp), encoded by the MDR1 gene, is the major player in the Multidrug resistance (MDR) phenotype in cancer cells. The human MDR1 gene is highly polymorphic, being the C3435T polymorphism the most studied one. However, MDR also occurs in cells that do not express Pgp, indicating that there are probably other MDR-inducing molecules in cancer cells. Cancer cells present the “Warburg effect” consisting in an increased glycolysis and lactic acid production, even in aerobic conditions. To prevent apoptosis by intracellular acidification, cancer cells up-regulate different pH regulators in the plasma membrane (PM) including the Vacuolar-ATPase (V-ATPase), creating an acidic tumor microenvironment, also associated with quimioresistance. V-ATPase and Pgp are ATP dependent, thus combining energy blockers with chemotherapy drugs would probably overcome MDR phenotype. We aimed to study different mechanisms involved in chemotherapy resistance. Firstly, we correlated the presence of MDR1 gene polymorphisms with its expression and with the cytotoxicity profiles of anti-tumoral treatment, in different cancer cell lines. We also investigated the role of other mechanisms, such as cell bioenergetics and tumor microenvironment.We assayed the sensitivity of different cancer cell lines to paclitaxel and doxorubicin. We observed higher resistance in cell expressing Pgp or V-ATPase at the PM. Additionally, the tumor cell lines presented different genotypes for MDR1, that correlate with drugs cytotoxicity. Concerning other mechanisms involved in the MDR phenotype, we observed that lower extracellular pH correlated to a higher resistance and V-ATPase expression, highlighting the importance of the pH regulators. We also observed that the use of bioenergetic inhibitors depleted cell ATP and sensitized the cells, especially the most resistant ones, to the studied chemotherapeutic drugs.

This work was funded by the projects CESPU-02-GBMC-CICS-11 and CESPU-03-GBMC-CICS-11