Up-regulation of MRP4 and down-regulation of influx transporters in human leukemic cells with acquired resistance to 6-mercaptopurine.
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.
Peng
Xing-Xiang
XX
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY 11439, United States.
Shi
Zhi
Z
Damaraju
Vijaya L
VL
Huang
Xiao-Cong
XC
Kruh
Gary D
GD
Wu
Hsiang-Chun
HC
Zhou
Ying
Y
Tiwari
Amit
A
Fu
Liwu
L
Cass
Carol E
CE
Chen
Zhe-Sheng
ZS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000032:analysis; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002460:Cell Line; D019008:Drug Resistance, Neoplasm; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors; D033722:Equilibrative-Nucleoside Transporter 2 / Q000037:antagonists & inhibitors; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000032:analysis; D015122:Mercaptopurine / Q000493:pharmacokinetics / Q000494:pharmacology*; D008780:Methyltransferases / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis / Q000502:physiology*; D009363:Neoplasm Proteins / Q000032:analysis; D033703:Nucleoside Transport Proteins / Q000032:analysis / Q000502:physiology*; D015854:Up-Regulation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; D007041:Hypoxanthine Phosphoribosyltransferase; D026901:Membrane Transport Proteins; D015122:Mercaptopurine; D008780:Methyltransferases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D033703:Nucleoside Transport Proteins; C073492:ABCC4 protein, human; C116614:ABCG2 protein, human; C438649:SLC29A1 protein, human; C438654:SLC29A2 protein, human; C065171:cif nucleoside transporter; C022745:thiopurine methyltransferase