title: Characterization and modulation of drug transport kinetics in K562 c1.6 daunorubicin-resistant cell line.
abstract: The effects of cyclosporin A (CSA) and cellular energy depletion on daunorubicin (DAU) transport kinetics were investigated in a human erythroid leukaemia cell line K562 c1.6 selected for resistance to daunorubicin. K562 c1.6/DAU resistant cells displayed high levels of P-glycoprotein and a high level of multidrug resistance against several antitumour drugs. The resistance factors of K562 c1.6/DAU cells to DAU, doxorubicin, vinblastine and etoposide were 106, 114, 85 and 13 respectively. A 1.6-fold decrease (P < 0.01, n = 8) in DAU accumulation and a 4-fold increase (P < 0.001, n = 8) in DAU efflux were shown in the resistant cells when compared to K562 c1.6 drug-sensitive parental cells. K562 c1.6/DAU cells were also shown to reach a DAU saturation level (SL) 8-fold faster (P < 0.001, n = 8) than the parental cells. Addition of CSA to the resistant cells led to a dose-dependent increase in cellular DAU retention, while no such effect was observed in the sensitive cells by the introduction of CSA. Resistance to the antitumour drugs could be reduced to various extents by CSA. The patterns of changes and modulations of DAU transport kinetics, as well as chemosensitivity in K562 c1.6/DAU cells were found to be similar to a vinblastine-resistant leukaemia cell line CEM/VLB100. However, K562 c1.6/DAU cells were more resistant to DAU, doxorubicin and etoposide than the CEM/VLB100 cells. An increase in DAU accumulation, intracellular SL and the time to reach 90% saturation level (SL90), and a decrease in DAU efflux in the resistant but not the sensitive cells were found in response to ATP depletion by sodium azide. These effects could be completely reversed by addition of glucose. Our results suggest that the presence of an energy-dependent effluxing mechanism responsible for the decreased drug accumulation and enhanced drug efflux may make a major contribution to the mechanism of resistance in K562 c1.6/DAU resistant cells.
authors.affiliation: Department of Haematology, London Hospital Medical College, London.
authors.forename: X R
authors.initials: XR
authors.lastname: Jiang
authors.forename: M G
authors.initials: MG
authors.lastname: Macey
authors.forename: P W
authors.initials: PW
authors.lastname: Collins
authors.forename: A C
authors.initials: AC
authors.lastname: Newland
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001386:Azides / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D003630:Daunorubicin / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004351:Drug Resistance; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology; D019810:Sodium Azide; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001386:Azides; D016572:Cyclosporine; D019810:Sodium Azide; D005947:Glucose; D003630:Daunorubicin