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

Marin M, Poret A, Maillet G, Leboulenger F, Le Foll F

Laboratory of Ecotoxicology UPRES-EA 3222, IFRMP 23, University of Le Havre, 25 rue Philippe Lebon, 76058 Le Havre cedex, France. matthieu.marin@univ-lehavre.fr

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 (MDR(REV)) 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 (I(Cl-swell)) in MDR-, MDR+, and MDR(REV) MCF7 cells. While verapamil inhibited I(Cl-swell) in all cell types, doxorubicin and vincristine rapidly and reversibly inhibited I(Cl-swell) uniquely in MDR+. Intracellular dialysis of MDR+ cells with C219 anti-P-gp antibody abolished the sensitivity of I(Cl-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 I(Cl-swell) in resistant MCF7.

Published 1 August 2005 in Biochem Biophys Res Commun, 334(4): 1266-78.
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