The leukotriene LTD4 receptor antagonist MK571 specifically modulates MRP associated multidrug resistance

Biochem Biophys Res Commun. 1995 Mar 8;208(1):345-52. doi: 10.1006/bbrc.1995.1344.


The multidrug resistant cell lines HL60/AR and GLC4/ADR show high overexpression of the gene encoding the multidrug resistance associated protein MRP compared to their drug sensitive parental counterparts. This and the virtual absence of mdr1/P-glycoprotein gene expression was proven by a complementary DNA polymerase chain reaction (cDNA-PCR) approach. Applying a 72-hour tetrazolium based colorimetric MTT-assay we demonstrate on both MDR sublines a dose-dependent modulation of drug resistances by the leukotriene LTD4 receptor antagonist MK571. A complete reversal of vincristine resistances was achieved at final MK571 concentrations of 30 microM (HL60/AR) or 50 microM (GLC4/ADR) which by itself did not disturb cellular proliferation. The drug resistance of a mdr1/P-gp overexpressing multidrug-resistant HL60 subline, in contrast, was not significantly affected by MK571. Similar effects were seen using the glutathione (GSH) synthesis inhibitor buthionine sulfoximine (BSO). Our results point to a relationship between MRP and a conjugate transporter and identify MK571 as a new tool structure for developing modulators specific for a MRP associated multidrug resistance.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • ATP-Binding Cassette Transporters / biosynthesis*
  • Base Sequence
  • Carcinoma, Small Cell
  • Cell Line
  • Cell Survival / drug effects
  • Clone Cells
  • DNA Primers
  • Daunorubicin / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple*
  • Gene Expression / drug effects
  • Humans
  • Leukemia, Promyelocytic, Acute
  • Leukotriene Antagonists*
  • Lung Neoplasms
  • Membrane Proteins*
  • Molecular Sequence Data
  • Multidrug Resistance-Associated Proteins
  • Polymerase Chain Reaction
  • Propionates / pharmacology*
  • Quinolines / pharmacology*
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Leukotriene*
  • Tumor Cells, Cultured
  • Vincristine / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • DNA Primers
  • Leukotriene Antagonists
  • Membrane Proteins
  • Multidrug Resistance-Associated Proteins
  • Propionates
  • Quinolines
  • Receptors, Immunologic
  • Receptors, Leukotriene
  • Vincristine
  • verlukast
  • cysteinyl leukotriene receptor 2
  • leukotriene D4 receptor
  • Daunorubicin