Regulation of volume-sensitive Cl− channels in multi-drug resistant MCF7 cells

The P-glycoprotein (P-gp) is thought to be involved in the regulation of volume-sensitive chloride channels. In this study, the possible coupling between P-gp and swelling-activated chloride channels has been examined in MCF7 cells with sensitive (MDR−), resistant (MDR+), and reversed resistant (MDRREV) phenotypes. Western blot analysis showed that incubation of cells with doxorubicin induced P-gp expression in a reversible manner. Exposure of MDR+ cells to hypotonicity resulted in an inhibition of P-gp activity while hypotonic challenges induced swelling-activated chloride currents (ICl-swell) in MDR−, MDR+, and MDRREV MCF7 cells. While verapamil inhibited ICl-swell in all cell types, doxorubicin and vincristine rapidly and reversibly inhibited ICl-swell uniquely in MDR+. Intracellular dialysis of MDR+ cells with C219 anti-P-gp antibody abolished the sensitivity of ICl-swell to doxorubicin and led to a response pattern very close to that of MDR− cells. Taken together, these results strongly suggest that the P-glycoprotein regulates ICl-swell in resistant MCF7.