Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux.

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Morrow CS, Peklak-Scott C, Bishwokarma B, Kute TE, Smitherman PK, Townsend AJ

Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux.

Mol Pharmacol. 2006 Apr;69(4):1499-505. Epub 2006 Jan 24.

PubMed ID

16434618 [ View in PubMed

]

Abstract

Based upon several previous reports, no consistent relationship between multidrug resistance protein 1 (MRP1, ABCC1) expression and cellular sensitivity to mitoxantrone (MX) toxicity can be ascertained; thus, the role of MRP1 in MX resistance remains controversial. The present study, using paired parental, MRP1-poor, and transduced MRP1-overexpressing MCF7 cells, unequivocally demonstrates that MRP1 confers resistance to MX cytotoxicity and that resistance is associated with reduced cellular accumulation of MX. This MRP1-associated reduced accumulation of MX was partially reversed by treatment of cells with 50 microM MK571 [3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl) methylsulfanyl] propionic acid]-an MRP inhibitor that increased MX accumulation in MRP1-expressing MCF7 cells but had no effect on MRP-poor MCF7 cells. Moreover, in vitro experiments using inside-out membrane vesicles show that MRP1 supports ATP-dependent, osmotically sensitive uptake of MX. Unlike ABCG2 (breast cancer resistance protein, mitoxantrone-resistant protein), MRP1-mediated MX transport is dependent upon the presence of glutathione or its S-methyl analog. In addition, MX stimulates transport of [3H]glutathione. Together, these data are consistent with the interpretation that MX efflux by MRP1 involves cotransport of MX and glutathione. The results suggest that MRP1-like the alternative MX transporters ABCG2 and ABCB1 (MDR1, P-glycoprotein)-can significantly influence tumor cell sensitivity to and pharmacological disposition of MX.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Mitoxantrone	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Substrate	Details
Mitoxantrone	Multidrug resistance-associated protein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Mitoxantrone	Multidrug resistance-associated protein 1	IC 50 (nM)	1.5	N/A	N/A	Details
Mitoxantrone	Multidrug resistance-associated protein 1	IC 50 (nM)	1.9	N/A	N/A	Details