Diverse effects of P-glycoprotein inhibitory agents on human leukemia cells expressing the multidrug resistance protein (MRP)

G Lehne, L Mørkrid, M den Boer, H E Rugstad

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

UNLABELLED: Multidrug resistance (MDR) to cancer chemotherapy is frequently associated with decreased drug accumulation in cancer cells due to drug expulsion by multidrug transporters such as P-glycoprotein (Pgp) and multidrug resistance protein (MRP). The novel resistance modifying agents PSC 833, 280-446, and LY 335979 are primarily targeted at inhibition of Pgp, and their MRP inhibitory potential is largely unknown.

OBJECTIVE: In the present study we addressed the effect of these agents on MRP-derived drug resistance.

MATERIALS: Drug-resistant human leukemia cells with Pgp+/MRP- (KG1a/200, K562/150) and Pgp-/MRP+ (HL60/130) phenotypes were maintained in suspension cultures for experimental studies of drug accumulation and drug sensitization by Pgp inhibitors.

METHODS: Intracellular accumulation of the fluorescent anthracycline daunorubicin was measured by flow cytometry and fluorescence detection. Daunorubicin dose-response curves were generated by non-linear regression of electronically measured cell counts of 72- - 96-h cultures. The half-maximal growth inhibitory dose (GI50) was used as measure of growth inhibition.

RESULTS: All MDR phenotypes studied exercised significant resistance to daunorubicin. PSC 833, 280-446 and LY335979 were equal in sensitizing Pgp+/MRP- cells to daunorubicin-induced growth inhibition (p < 0.0001). The Pgp-/MRP+ cells responded to PSC 833 and 280-446 by increased accumulation of daunorubicin (p = 0.0022 and p = 0.0005, respectively) and sensitization to the drug (p = 0.0009 and p = 0.0007, respectively). Conversely, LY335979 did not affect accumulation of daunorubicin in Pgp-/MRP+ cells nor sensitize these cells to daunorubicin.

CONCLUSION: Pgp inhibitory agents have differential effects on MRP-derived drug resistance which could be exploited in treatment of multidrug resistance in cancer patients.

Original languageEnglish
Pages (from-to)187-95
Number of pages9
JournalInternational journal of clinical pharmacology and therapeutics
Volume38
Issue number4
DOIs
Publication statusPublished - Apr 2000
Externally publishedYes

Keywords

  • ATP Binding Cassette Transporter, Subfamily B/drug effects
  • Antibiotics, Antineoplastic/metabolism
  • Antineoplastic Agents/pharmacology
  • Cyclosporins/pharmacology
  • Daunorubicin/metabolism
  • Dibenzocycloheptenes/pharmacology
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Fluorescence
  • Humans
  • Leukemia, Myeloid/metabolism
  • Peptides, Cyclic/pharmacology
  • Quinolines/pharmacology
  • Tumor Cells, Cultured/drug effects

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