Modulation by LY335979 of P-glycoprotein function in multidrug-resistant cell lines and human natural killer cells.
Resistance to chemotherapy by some human tumors may be due to overexpression of membrane-associated transport proteins. The best characterized of these is the multidrug resistance (MDR) transporter, P-glycoprotein (Pgp). The aim of this study was to measure the inhibitory effects of a potent new MDR modulator, (2R)-anti-5-(3-[4-(10,11-difluoromethanodibenzo-suber-5-yl) piperazin-1-yl]-2-hydroxypropoxy)quinoline trihydrochloride (LY335979), in the drug-resistant cell line HL60/VCR and in normal, human CD56(+) lymphocytes. We used flow cytometric methods to detect the accumulation of rhodamine 123 and daunorubicin, fluorescent MDR substrates, in these cells. Our results indicate that LY335979 was 500-1500 times more potent than cyclosporin A or verapamil in restoring Pgp substrate accumulation in the MDR cell line HL60/VCR. Moreover, LY335979 could effectively block Pgp function on isolated CD56(+) lymphocytes (IC(50) = 1.2 nM) or CD56(+) lymphocytes in whole blood (IC(50) = 174 nM). We conclude that LY335979 is among the most potent Pgp inhibitors described and that it maintains significant potency in whole-human blood. These latter findings are important for establishing the dosing regimens of LY335979 for future clinical studies.
Green
L J
LJ
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. green_lisa_j@lilly.com
Marder
P
P
Slapak
C A
CA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000502:physiology*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D003630:Daunorubicin / Q000378:metabolism; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D005456:Fluorescent Dyes / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003986:Dibenzocycloheptenes; D005456:Fluorescent Dyes; D011804:Quinolines; D020112:Rhodamine 123; C095179:zosuquidar trihydrochloride; D003630:Daunorubicin