Coordinated action of glutathione S-transferases (GSTs) and multidrug resistance protein 1 (MRP1) in antineoplastic drug detoxification. Mechanism of GST A1-1- and MRP1-associated resistance to chlorambucil in MCF7 breast carcinoma cells.
To examine the role of multidrug resistance protein 1 (MRP1) and glutathione S-transferases (GSTs) in cellular resistance to antineoplastic drugs, derivatives of MCF7 breast carcinoma cells were developed that express MRP1 in combination with one of three human cytosolic isozymes of GST. Expression of MRP1 alone confers resistance to several drugs representing the multidrug resistance phenotype, drugs including doxorubicin, vincristine, etoposide, and mitoxantrone. However, co-expression with MRP1 of any of the human GST isozymes A1-1, M1-1, or P1-1 failed to augment MRP1-associated resistance to these drugs. In contrast, combined expression of MRP1 and GST A1-1 conferred approximately 4-fold resistance to the anticancer drug chlorambucil. Expression of MRP1 alone failed to confer resistance to chlorambucil, showing that the observed protection from chlorambucil cytotoxicity was absolutely dependent upon GST A1-1 protein. Moreover, using inhibitors of GST (dicumarol) or MRP1 (sulfinpyrazone), it was shown that in MCF7 cells resistance to chlorambucil requires both intact MRP1-dependent efflux pump activity and, for full protection, GST A1-1 catalytic activity. These results are the first demonstration that GST A1-1 and MRP1 can act in synergy to protect cells from the cytotoxicity of a nitrogen mustard, chlorambucil.
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. cmorrow@wfubmc.edu
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CS
Morrow
P K
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Smitherman
S K
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Diah
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Schneider
A J
AJ
Townsend
D000970:Antineoplastic Agents / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D002699:Chlorambucil / Q000378:metabolism / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000378:metabolism*; D001728:Dicumarol / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005978:Glutathione / Q000032:analysis / Q000493:pharmacokinetics; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D013442:Sulfinpyrazone / Q000494:pharmacology; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002699:Chlorambucil; D004268:DNA-Binding Proteins; D001728:Dicumarol; D004791:Enzyme Inhibitors; D005978:Glutathione; D005982:Glutathione Transferase; D007527:Isoenzymes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D013442:Sulfinpyrazone; C078444:MSH3 protein, human; C421109:multidrug resistance-associated protein 1