Reversal of MRP-mediated multidrug resistance in human lung cancer cells by the antiprogestatin drug RU486

Multidrug resistance-associated protein (MRP) and P-glycoprotein (P-gp) are drug efflux pumps conferring multidrug resistance to tumor cells. RU486, a n antiprogestatin drug known to inhibit P-gp function, was examined for its effect on MRP activity in MRP-overexpressing lung tumor GLC4/Sb30 cells. I n such cells, the antihormone compound was found to increase intracellular accumulation of calcein, a fluorescent compound transported by MRP, in a do se-dependent manner, through inhibition of cellular export of the dye; in c ontrast, it did not alter calcein levels in parental GLC4 cells. RU486, whe n used at 10 mu M, a concentration close to plasma concentrations achievabl e in humans, strongly enhanced the sensitivity of GLC4/Sb30 cells towards t wo known cytotoxic substrates of MRP, the anticancer drug vincristine and t he heavy metal salt potassium antimonyl tartrate. Vincristine accumulation levels were moreover up-regulated in RU486-treated GLC4/Sb30 cells. In addi tion, such cells were demonstrated to display reduced cellular levels of gl utathione which is required for MRP-mediated transport of some anticancer d rugs. These findings therefore demonstrate that RU486 can down-modulate MRP -mediated drug resistance, in addition to that linked to P-gp, through inhi bition of MRP function (C) 1999 Academic Press.