INHIBITION OF P-GLYCOPROTEIN ACTIVITY IN HUMAN LEUKEMIC-CELLS BY MIFEPRISTONE

The antiprogestatin drug mifepristone has previously been shown to pot entiate anti-cancer drug activity in rodent multidrug-resistant cell l ines through inhibition of P-glycoprotein (P-gp) function. In order to characterize P-gp-mifepristone interactions in human tumoral cells, w e have studied the effect of the antiprogestatin agent on P-gp activit y in human CD34(+) leukemic cells known to display high levels of P-gp -related drug efflux. P-gp-mediated transport of the fluorescent dye r hodamine 123 occurring in the CD34(+) KG1a myeloid leukemia cell line was found to be strongly inhibited by mifepristone in a dose-dependent manner. Similarly to verapamil, a well-known chemosensitizer agent, t he antiprogestatin drug increased doxorubicin cytotoxicity in KG1a cel ls. Mifepristone, when used at a 10 mu M concentration thought to be a chievable in vivo without major toxicity, was also able to markedly de crease cellular rhodamine 123 efflux occurring in CD34(+) blast cells isolated from six patients suffering from myeloid acute leukemias. The se results thus indicate that mifepristone can strongly inhibit P-gp a ctivity in human cells, including tumoral cells freshly isolated from patients, therefore suggesting that the clinical use of this compound may contribute to down-modulate P-gp-mediated drug resistance.