COLLATERAL SENSITIVITY OF MULTIDRUG-RESISTANT CELLS TO NARCOTIC ANALGESICS IS DUE TO EFFECTS ON THE PLASMA-MEMBRANE

It has previously been demonstrated that opiates interact directly with P-glycoprotein in drug resistant Chinese hamster ovary (CHO) cells (Callaghan, R. and Riordan, J.R. (1993) J. Biol. Chem. 268, 16059-16064). In this study we have examined the effects of several opiates on the growth of drug sensitive and resistant CHO and human MCF7 cell lines. The growth of P-glycoprotein expressing cells was inhibited by the opiates pentazocine, pethidine and naloxone to a greater extent than in drug sensitive cells. Since P-glycoprotein is localised at the plasma membrane the effects of opiates on membrane biophysical properties were investigated. The opiates caused a fluidizing effect in membranes from P-glycoprotein expressing cells and decreased the basal level of P-glycoprotein phosphorylation. In addition, they were able to increase the leakage of the membrane impermeant compound 6-carboxyfluorescein entrapped in model membrane vesicles. The ability to alter membrane biophysical properties correlated with the inhibitory effects on growth of drug resistant cells. These results suggest that the collateral sensitivity of P-glycoprotein expressing cell lines to opiates is mediated by the drugs' effects on the plasma membrane.