The leukotriene LTD4 receptor antagonist MK571 specifically modulates MRP associated multidrug resistance.
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.
Gekeler
V
V
Byk Gulden, Konstanz, Germany.
Ise
W
W
Sanders
K H
KH
Ulrich
W R
WR
Beck
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D001483:Base Sequence; D018288:Carcinoma, Small Cell; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D017931:DNA Primers; D003630:Daunorubicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D020024:Leukotriene Antagonists; D008175:Lung Neoplasms; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016133:Polymerase Chain Reaction; D011422:Propionates / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018077:Receptors, Leukotriene; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D003630:Daunorubicin; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D014750:Vincristine; C059141:verlukast; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor