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Expression and function of multidrug resistance P-glycoprotein in a cultured natural killer cell-rich population revealed by MRK16 monoclonal antibody and AHC-52.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 1994 Oct 18; Vol. 48 (8), pp. 1641-6. - Publication Year :
- 1994
-
Abstract
- Natural killer (NK) cells have been reported recently to be the highest in expressing multidrug resistance (MDR) P-glycoprotein among normal mature lymphoid cells. Using a cultured NK cell-rich population, we have examined the expression and function of P-glycoprotein, in particular its role in NK cell-mediated cytotoxicity, by employing two MDR-reversing agents (nicardipine and AHC-52, a nicardipine analog almost devoid of calcium channel blocking activity) and monoclonal antibody against P-glycoprotein (MRK-16). The expression of P-glycoprotein was detected by flow cytometry and polymerase chain reaction of reverse transcribed mRNA. P-glycoprotein was functional in terms of rhodamine dye excretion and its susceptibility to the MDR-reversing agents. Since the concentration of nicardipine required for 50% inhibition (IC50) of rhodamine dye excretion (2 microM) was close to that of AHC-52 (5 microM), it was suggested that their inhibitory effects were not due to calcium channel blocking activity, and that ACH-52 is a selective inhibitor for P-glycoprotein. The IC50 of nicardipine for NK cell-mediated cytotoxicity (33 microM) was also close to that of AHC-52 (26 microM), indicating that P-glycoprotein is involved in NK cell-mediated cytotoxicity. In support of this, MRK16 inhibited NK cell-mediated cytotoxicity in a concentration-dependent manner. Both binding of target cells to NK cells and post-binding events were affected by AHC-52, suggesting that P-glycoprotein is involved in several steps in NK cell-mediated cytotoxicity.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics
Antibodies, Monoclonal
Base Sequence
Cells, Cultured
Cytotoxicity, Immunologic drug effects
Drug Resistance
Flow Cytometry
Humans
Immunoglobulin Fab Fragments pharmacology
Killer Cells, Natural drug effects
Killer Cells, Natural immunology
Molecular Sequence Data
Polymerase Chain Reaction
Rhodamine 123
Rhodamines
ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
ATP Binding Cassette Transporter, Subfamily B, Member 1 physiology
Dihydropyridines pharmacology
Killer Cells, Natural metabolism
Pyrazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2952
- Volume :
- 48
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 7980629
- Full Text :
- https://doi.org/10.1016/0006-2952(94)90209-7