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Modulation by LY335979 of P-glycoprotein function in multidrug-resistant cell lines and human natural killer cells
L J Green1, P Marder, C A Slapak
1Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. green_lisa_j@lilly.com
Abstract:
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.
Insights
A new drug, LY335979, is a highly potent inhibitor of P-glycoprotein (Pgp), a transporter protein linked to multidrug resistance (MDR) in cancer. It effectively blocks Pgp function in both isolated cells and whole blood, showing promise for clinical applications.
Area of Science:
- Pharmacology
- Molecular Biology
- Cancer Research
Background:
- Multidrug resistance (MDR) in human tumors is often mediated by efflux pumps like P-glycoprotein (Pgp).
- Developing effective modulators of Pgp is crucial for overcoming chemotherapy resistance.
Purpose of the Study:
- To evaluate the efficacy of a novel Pgp inhibitor, LY335979, in overcoming MDR.
- To assess the potency of LY335979 in drug-resistant cell lines and normal human lymphocytes.
Main Methods:
- Utilized flow cytometry to measure the intracellular accumulation of fluorescent MDR substrates (rhodamine 123 and daunorubicin).
- Tested LY335979 in the multidrug-resistant HL60/VCR cell line and in normal human CD56(+) lymphocytes.
- Determined IC50 values for Pgp inhibition in isolated cells and whole blood.
Main Results:
- LY335979 demonstrated 500-1500 times greater potency than cyclosporin A or verapamil in restoring Pgp substrate accumulation in HL60/VCR cells.
- LY335979 effectively inhibited Pgp function in isolated CD56(+) lymphocytes (IC50 = 1.2 nM) and in whole blood (IC50 = 174 nM).
Conclusions:
- LY335979 is one of the most potent P-glycoprotein inhibitors identified to date.
- The significant potency of LY335979 in whole human blood is critical for guiding future clinical dosing strategies.
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