Intracellular P-gp contributes to functional drug efflux and resistance in acute myeloid leukaemia

Leuk Res. 2001 May;25(5):395-405. doi: 10.1016/s0145-2126(00)00156-9.

Abstract

Drug compartmentalization as well as drug efflux can contribute to drug resistance. We demonstrate the presence of P-gp in intracellular vesicles in certain AML cell lines and show localization of DNR to a similar subcellular compartment(s) that can be altered in the presence of P-gp inhibitors. Analysis of leukaemic cell lines and 50 AML patient samples showed that the level of P-gp mRNA or total P-gp protein correlated better with drug efflux than surface P-gp protein, suggesting that intracellular P-gp may contribute to MDR in AML. Therefore, the level of total P-gp protein or mRNA may be a better indicator of MDR than surface P-gp protein. In addition, we provide evidence for a novel mechanism of drug sequestration in K562 myeloid leukaemic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP-Binding Cassette Transporters / metabolism
  • Acute Disease
  • Antibiotics, Antineoplastic / pharmacokinetics*
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Death / drug effects
  • Cell Survival
  • Cyclosporine / pharmacology
  • Daunorubicin / pharmacokinetics*
  • Daunorubicin / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Resistance, Multiple
  • Flow Cytometry
  • HL-60 Cells
  • Humans
  • K562 Cells
  • Leukemia, Myeloid / drug therapy
  • Leukemia, Myeloid / metabolism*
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Vault Ribonucleoprotein Particles / metabolism
  • Verapamil / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Antibiotics, Antineoplastic
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • RNA, Messenger
  • Vault Ribonucleoprotein Particles
  • major vault protein
  • Cyclosporine
  • Verapamil
  • Daunorubicin