The specific bisindolylmaleimide PKC-inhibitor GF 109203X efficiently modulates MRP-associated multiple drug resistance.
The newly identified drug transporter MRP is functionally linked to a multiple drug resistance independent from P-glycoprotein. Resistance modifiers for this type of MDR are rare at present. We analyzed the modulating effect of the highly selective bisindolylmaleimide PKC inhibitor GF 109203X on the MRP overexpressing human MDR sublines HL60/AR and GLC4/ADR. Applying a 72 hour MTT-assay we demonstrate a complete reversal of the vincristine resistance of HL60/AR cells. Adriamycin resistance of HL60/AR, or vincristine resistance of GLC4/ADR were partially reversed. Furthermore, rhodamine 123 efflux from HL60/AR was strongly modulated by GF 109203X. Since the PKC inhibitor did not significantly influence MRP gene expression at the mRNA level which was examined by cDNA-PCR, our results suggest either a direct interaction of the compound with MRP or/and an indirect influence on MRP activity via altering the phosphorylation status of the transporter.
Gekeler
V
V
Byk Gulden, Konstanz, Germany.
Boer
R
R
Ise
W
W
Sanders
K H
KH
Schächtele
C
C
Beck
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D008301:Maleimides / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000633:toxicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D007211:Indoles; D008301:Maleimides; D012235:Rhodamines; D020112:Rhodamine 123; D014750:Vincristine; D004317:Doxorubicin; D011493:Protein Kinase C; C070515:bisindolylmaleimide I