title: Folates provoke cellular efflux and drug resistance of substrates of the multidrug resistance protein 1 (MRP1).
abstract: Cellular folate concentration was earlier reported to be a critical factor in the activity and expression of the multidrug resistance protein MRP1 (ABCC1). Since MRP1 mediates resistance to a variety of therapeutic drugs, we investigated whether the cellular folate concentration influences the MRP1-mediated cellular resistance against drugs. As a model system, we used the human ovarian carcinoma cell line 2008wt, and its stably MRP1/ABCC1-transfected subline 2008/MRP1. These cell types have a moderate and high expression of MRP1, respectively. In folate-deprived 2008/MRP1 cells, the MRP1-mediated efflux of its model substrate calcein decreased to ~55 % of the initial efflux rate under folate-rich conditions. In 2008wt cells, only a small decrease in efflux was observed. Folate depletion for 5-10 days markedly increased (~500 %) cellular steady-state accumulation of calcein in 2008/MRP1 cells and moderately in 2008wt cells. A subsequent short (24 h) exposure to 2.3 μM L-leucovorin decreased calcein levels again in MRP1-overexpressing cells. Folate deprivation markedly increased growth inhibitory effects of the established MRP1 substrates daunorubicin (~twofold), doxorubicin (~fivefold), and methotrexate (~83-fold) in MRP1-overexpressing cells, proportional to MRP1 expression. In conclusion, this study demonstrates that increased cellular folate concentrations induce MRP1/ABCC1-related drug efflux and drug resistance. These results have important implications in the understanding of the role of MRP1 and its homologs in clinical drug resistance.
authors.affiliation: Department of Clinical Chemistry, Slotervaartziekenhuis Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan Hendrik
authors.initials: JH
authors.lastname: Hooijberg
authors.forename: Gerrit
authors.initials: G
authors.lastname: Jansen
authors.forename: Ietje
authors.initials: I
authors.lastname: Kathmann
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Adrie C
authors.initials: AC
authors.lastname: Laan
authors.forename: Ina
authors.initials: I
authors.lastname: van Zantwijk
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D001692:Biological Transport; D045744:Cell Line, Tumor; D004351:Drug Resistance / Q000187:drug effects*; D005492:Folic Acid / Q000378:metabolism; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects* / Q000378:metabolism
chemical_list: D005492:Folic Acid; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins