Reversal of multidrug resistance in HL-60 cells by verapamil and liposome-encapsulated doxorubicin.
The means of circumventing multidrug resistance was investigated in HL-60 and HL-60R (a drug resistance variant) cell lines. The HL-60R cell line was developed from the parent line by serial exposure to increasing concentrations of doxorubicin over a 4-month period. This drug resistant cell line expressed P-glycoprotein in its cell surface and is 80-fold more resistant than the parent cell line. Multidrug resistance, as evaluated by a cell cytotoxicity assay using doxorubicin, can be overcome by use of verapamil. Multidrug resistance can also be circumvented when doxorubicin is encapsulated in liposomes. The combination of verapamil and doxorubicin-encapsulated liposomes does enhance circumvention of multidrug resistance beyond the effect of each agent alone, implying a synergistic effect. The lipid composition of the liposomes does affect the rate of drug uptake but not the overall cytotoxic effect of doxorubicin. The synergistic reversal of multidrug resistance by doxorubicin-encapsulated liposomes and verapamil suggests a multifactorial basis for drug resistance in this cell line.
Department of Medicine, University of Kansas Medical Center, Kansas City 66103.
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Sadasivan
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Morgan
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Fabian
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Stephens
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002462:Cell Membrane / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D008081:Liposomes; D008562:Membrane Glycoproteins / Q000032:analysis; D010641:Phenotype; D011289:Preleukemia / Q000737:chemistry* / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008081:Liposomes; D008562:Membrane Glycoproteins; D004317:Doxorubicin; D014700:Verapamil