Evaluation of indomethacin and dexamethasone effects on BCRP-mediated drug resistance in MCF-7 parental and resistant cell lines

Abstract

Breast cancer resistance protein is a member of the ATP-binding cassette transporter G family that extrudes xenotoxins from cells, mediating drug resistance, and has been recognized as a major cause of failure of various carcinoma chemotherapies. In this study, the modulatory effects of dexamethasone and indomethacin on the cell cytotoxicity of mitoxantrone and on the BCRP protein activity in breast cancer cell lines were examined. MCF cells were seeded at 1 x 10(4) cells per well in 96-well flat-bottomed microplates for 48 hours and treated with increasing doses of dexamethasone, indomethacin, and novobiocin alone or preincubated with increasing doses of the drugs and then coexposed to mitoxantrone. Cell viability was measured after 1-4 days, using the MTT assay. BCRP activity was determined flow cytometrically by measuring mitoxantrone accumulation in the absence and presence of the inhibitor, novobiocin. Cotreatment of mitoxantrone with different concentrations of dexamethasone and indomethacin sensitized parental and resistant MCF-7 cells to mitoxantrone cytotoxicity. Dexamethasone increased the accumulation of mitoxantrone in the MCF-7/MX cell line, indicating an inhibition of BCRP. In spite of increased levels of mitoxantrone cytotoxicity in the presence of indomethacin, the accumulation of mitoxantrone was not increased in indomethacin-treated MCF cells.