Over-expression of multidrug resistance P-glycoprotein inhibits NK granule-mediated lytic ability without affecting the Fas lytic pathway.

Multidrug resistance (MDR) in tumor cells is commonly associated wich the over-expression of P-glycoprotein (Pgp), the product of the MDR1 gene. In this study, we investigated whether over-expression of Pgp in natural killer (NK) cells would influence their granule- as well as fas-mediated cytolytic activities. YT-INDY, a human NK-like cell line, was transfected with the MDR 1 gene, then tested for Pgp activity the presence of various concentrations of R-verapamil, a potent Pgp inhibitor. We showed that, unlike control YT-INDY, the Pgp activity of the transfectants (YT-mdr(+)) was only partially inhibited by R-verapamil. We also showed that Fas lytic activity was unaltered and that the loss of granule-mediated cytotoxicity was not due to reduced LFA-1 expression or to a decrease in target cell (TC) binding. Our data indicate that Pgp may be involved in the release of cytotoxic molecules.