title: Up-regulation of P-glycoprotein confers acquired resistance to 6-mercaptopurine in human chronic myeloid leukemia cells.
abstract: To investigate the mechanisms of cellular resistance to 6-mercaptopurine (6-MP) in chronic myeloid leukemia (CML), a 6-MP resistant cell line (K562-MP5) was established by stepwise selection of the CML cell line (K562). The results of the drug sensitivity analysis of the K562-MP5 cell line revealed the cells to be 339-fold more resistant to 6-MP compared with the parental K562 cells. K562-MP5 cells exhibited decreased accumulation and increased efflux of [(14)C]6-MP and its metabolites. In addition, K562-MP5 cells showed increased [(3)H]MTX transport. K562-MP5 cells over-expressed P-glycoprotein (P-gp) and up-regulated MDR1 mRNA levels. Taken together, these results suggest that the up-regulation of P-gp, which contributes to the decreased accumulation by increasing the efflux of 6-MP and its metabolites, underlies the mechanism of 6-MP resistance in K562 cells.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439, USA.
authors.forename: Xing-Xiang
authors.initials: XX
authors.lastname: Peng
authors.forename: Zhi
authors.initials: Z
authors.lastname: Shi
authors.forename: Amit K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: Vijaya L
authors.initials: VL
authors.lastname: Damaraju
authors.forename: Liwu
authors.initials: L
authors.lastname: Fu
authors.forename: Carol E
authors.initials: CE
authors.lastname: Cass
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Gary D
authors.initials: GD
authors.lastname: Kruh
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen