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Diverse multidrug-resistance-modification agents inhibit cytolytic activity of natural killer cells
A S Chong1, P N Markham, H M Gebel
1Department of General Surgery, Rush-Presbyterian, St. Luke's Medical Center, Chicago, IL 60612.
Abstract:
Multidrug resistance (MDR) is the phenomenon in which cultured tumor cells selected for resistance to one chemotherapeutic agent simultaneously acquire resistance to several apparently unrelated drugs. MDR in tumor cells is associated with the over-expression of P-glycoprotein, an ATP-dependent cell-membrane transport molecule. P-glycoprotein is also expressed in several normal tissues but its physiological role(s) is unknown. We recently observed that a hierarchy of MDR-like activity exists among human peripheral blood lymphocytes in the order CD8 > CD4 > CD20 (cytotoxic/suppressor T cells, helper T cells and B cells respectively). In this study, we report that natural killer (NK) cells also express MDR-like activity. This activity could be inhibited with verapamil or solutol HS-15, two agents that reverse MDR in tumor cells. These, and four additional reversing agents, were used to investigate the possible role of P-glycoprotein in NK cells. We observed that at 10% of their IC50, five of six reversing agents inhibited NK-cell-mediated cytotoxicity; at higher (but non-toxic) doses, all six agents were inhibitory. These data suggest that NK-cell-mediated cytotoxicity may require the functional expression of an efflux molecule similar or identical to P-glycoprotein.
Insights
Natural killer (NK) cells exhibit multidrug resistance (MDR)-like activity. This activity, potentially involving P-glycoprotein, is crucial for NK cell-mediated cytotoxicity and can be modulated by MDR-reversing agents.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) in tumor cells is linked to P-glycoprotein, an efflux transporter.
- P-glycoprotein is present in normal tissues, but its function is unclear.
- Previous research indicated MDR-like activity in human lymphocytes (CD8, CD4, CD20 cells).
Purpose of the Study:
- To investigate MDR-like activity in natural killer (NK) cells.
- To explore the potential role of P-glycoprotein in NK cell function.
- To determine if MDR-reversing agents affect NK cell-mediated cytotoxicity.
Main Methods:
- Assessed MDR-like activity in NK cells.
- Utilized verapamil and solutol HS-15 to inhibit MDR-like activity.
- Tested the effect of six MDR-reversing agents on NK cell-mediated cytotoxicity at varying doses.
Main Results:
- NK cells demonstrate MDR-like activity.
- This activity is sensitive to inhibition by verapamil and solutol HS-15.
- Five of six MDR-reversing agents inhibited NK cell cytotoxicity at low doses, and all six inhibited at higher, non-toxic doses.
Conclusions:
- NK cells possess MDR-like activity.
- NK cell-mediated cytotoxicity may depend on a functional efflux molecule akin to P-glycoprotein.
- MDR-reversing agents can impair NK cell cytotoxic function.