Abstract
To investigate the mechanism of cellular resistance to 6-MP, we established a 6-MP resistant cell line (CEM-MP5) by stepwise selection of the human T-lymphoblastic leukemia cell line (CEM). CEM-MP5 cells were about 100-fold resistant to 6-MP compared with parental CEM cells. Western blot analysis demonstrated that multidrug resistant protein 4 (MRP4) was increased in CEM-MP5 cells, whereas the levels of the nucleoside transporters hENT1, hCNT2 and hCNT3 were decreased compared with those of parental CEM cells. Consistent with the operation of an efflux pump, accumulation of [14C]6-MP and/or its metabolites was reduced, and ATP-dependent efflux was increased in CEM-MP5 cells. Taken together these results showed that up-regulation of MRP4 and down-regulation of influx transporters played a major role in 6-MP resistance of CEM-MP5 cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / analysis
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / analysis
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Antimetabolites, Antineoplastic / pharmacology*
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Cell Line
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Drug Resistance, Neoplasm
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Equilibrative Nucleoside Transporter 1 / antagonists & inhibitors
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Equilibrative-Nucleoside Transporter 2 / antagonists & inhibitors
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Humans
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Hypoxanthine Phosphoribosyltransferase / metabolism
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Leukemia / drug therapy*
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Leukemia / metabolism
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Membrane Transport Proteins / analysis
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Mercaptopurine / pharmacokinetics
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Mercaptopurine / pharmacology*
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Methyltransferases / metabolism
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Multidrug Resistance-Associated Proteins / analysis
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Multidrug Resistance-Associated Proteins / physiology*
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Neoplasm Proteins / analysis
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Nucleoside Transport Proteins / analysis
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Nucleoside Transport Proteins / physiology*
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Up-Regulation
Substances
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ABCC4 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Antimetabolites, Antineoplastic
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Equilibrative Nucleoside Transporter 1
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Equilibrative-Nucleoside Transporter 2
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Membrane Transport Proteins
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Multidrug Resistance-Associated Proteins
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Neoplasm Proteins
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Nucleoside Transport Proteins
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SLC29A1 protein, human
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SLC29A2 protein, human
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cif nucleoside transporter
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Mercaptopurine
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Methyltransferases
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thiopurine methyltransferase
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Hypoxanthine Phosphoribosyltransferase