Epoxide metabolite of quinine and inhibition of the multidrug resistance pump in human leukemic lymphoblasts.
Multidrug resistance (MDR) in neoplastic cells is usually due to decreased cellular retention of drugs such as vincristine or doxorubicin. An ATP-dependent drug efflux pump has been detected in MDR-1-phenotypic cells; inhibition of the MDR pump is probably the primary mechanism for reversal of MDR. Although quinine (SQ1) and quinidine are reversal agents and inhibitors of the MDR pump, the results from in vivo experiments and in vitro experiments with these diastereomers are contradictory. These observations suggest that an oxidized metabolite of SQ1 is a more potent inhibitor of the MDR pump than is the parent compound. The chemical synthesis of the epoxides of SQ1 and quinidine is reported. The epoxy compounds have been tested as inhibitors of the ATP-dependent MDR pump in human CEM/VLB100 cells. The procedure is based on preloading the cells with an inhibitor and a low concentration of a substrate, rhodamine 123 (R123). After several cold rinses, the cell suspension is passed through a filtration-flow apparatus and the R123 in the filtrate (determined by fluorescence measurements) reveals the initial efflux of R123 through the MDR pump. When tested as an inhibitor of the MDR pump, quinine-10,11-epoxide is approximately 8-fold more potent than SQ1.
Wigler
P W
PW
Department of Medical Biology, University of Tennessee Medical Center/Knoxville 37920.
Lyon
K L
KL
Patterson
F K
FK
La Loggia
A J
AJ
Diaz-Araúzo
H
H
Reddy
M S
MS
Cook
J M
JM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D018432:Drug Resistance, Multiple; D004852:Epoxy Compounds / Q000378:metabolism; D006801:Humans; D007945:Leukemia, Lymphoid / Q000378:metabolism; D010084:Oxidation-Reduction; D011802:Quinidine / Q000009:adverse effects*; D011803:Quinine / Q000009:adverse effects* / Q000031:analogs & derivatives; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D004852:Epoxy Compounds; D012235:Rhodamines; D020112:Rhodamine 123; D011803:Quinine; D011802:Quinidine