Resistance of human multidrug resistance-associated protein 1-overexpressing lung tumor cells to the anticancer drug arsenic trioxide

The human multidrug-resistance protein (MRP1) confers resistance to some he avy metals such as arsenic and antimony, mainly through mediating an increa sed cellular efflux of metal. However, it was recently suggested that arsen ic, used under its trioxide derivative form as anticancer drug, is not hand led by MRP1. The aim of the present study was to test this hypothesis in MR P1-overexpressing human lung tumor GLC4/Sb30 cells. Using the cytotoxicity MTT assay, CLC4/Sb30 cells were found to be 10.8-fold more resistant to ars enic trioxide (As2O3) than parental GLC4 cells. MK571, a potent inhibitor o f MRP1 activity, almost totally reversed resistance of GLC4/Sb30 cells, but did not alter the sensitivity of GLC4 cells. Moreover, As2O3-loaded GLC4/S b30 cells poorly accumulated arsenic through an increased MK571-sensitive e fflux of metal. Finally, depletion of cellular glutathione levels in buthio nine sulfoximine-treated CLC4/Sb30 cells was found to result in increased a ccumulation and reduced efflux of arsenic in cells exposed to As2O3, outlin ing the glutathione-dependence of MRP1-mediated transport of the metal. The se results indicate that MRP1 overexpression in human tumor cells can confe r resistance to As2O3, which may limit the clinical use of this anticancer drug for treatment of MRP1-positive tumors. (C) 2001 Elsevier Science Inc. All rights reserved.