REVERSAL OF MULTIDRUG-RESISTANCE BY VALINOMYCIN IS OVERCOME BY CCCP

Reversal of P-glycoprotein-mediated multidrug resistance by valinomyci n is overcome by the proton ionophore, CCCP. This effect, a complete s uppression of the 5- to 10-fold valinomycin-induced reversal (''re-rev ersal''), exhibits a sharp extracellular potassium concentration ([K-o (+)]) dependence. It is observed at [K-o(+)] > 2-4 mM and not at [K-o( +)] less than or equal to 2 mM, in the case of the fluorescent substra tes rhodamine 123 and daunorubicin. The fact that ''re-reversal'' is d etected only for the combination of CCCP with valinomycin raises the p ossibility that a direct interaction between these ionophores may expl ain the phenomenon. We show spectroscopic evidence of such an interact ion, with a [K-o(+)]-dependence similar to that of the ''re-reversal.' ' These data suggest that the reversal of P-glycoprotein activity by v alinomycin can be compromised by anionic compounds such as CCCP due to complex formation. More generally, molecular interactions involving P -glycoprotein substrates or reversing agents may significantly affect drug accumulation in multidrug resistant cells. (C) 1996 Academic Pres s, Inc.