Susceptibility to LAK-mediated Cytotoxicity of Multidrug-resistant Variants of the Human RAJI Cell Line is Not Related to Expression of Major Cellular Adhesion Molecules

Abstract

The association of multidrug resistance (MDR) with resistance to lysis by natural killer (NK) and lymphokine-activated killer (LAK) cells is controversial. To address this issue further, drug-resistant variants of a human Burkitt lymphoma cell line (RAJI) were developed in vitro by intermittent exposure to Adriamycin® (R/ADR) or to etoposide (R/VP-16). The RAJI cell line was selected because it is a standard LAK-susceptible target. Both MDR lines as well as the parent cell line were found to be resistant to NK-mediated lysis, but highly susceptible to LAK-mediated lysis. Notably, R/ADR cells, which express high levels of P-glycoprotein (P-gp), were nearly eight-times more susceptible to LAK-mediated lysis than parental cells, whereas R/VP-16 cells, which are P-gp-negative, were equally as susceptible as parental cells. Immunofluorescence analyses revealed that expression of cellular adhesion molecules that have been reported to control susceptibility of targets to NK- and LAK-lysis (ICAM-1, LFA-1, LFA-3, and MHC class I) did not differ significantly between the RAJI parent line and drug-resistant variants. This finding suggests that the increased LAK-sensitivity of R/ADR results from alterations which affect postbinding stages of the LAK lytic pathway.