Reversal of P-glycoprotein-mediated multidrug resistance by valinomycin is overcome by die proton ionophore, CCCP. This effect, a complete suppression of the 5- to 10-fold valinomycin-induced reversal ('re-reversal'), exhibits a sharp extracellular potassium concentration ([K+(o)]) dependence. It is observed at [K+(o)] > 2-4 mM and not at [K+(o)] ≤ 2 mM, in the case of the fluorescent substrates rhodamine 123 and daunorubicin. The fact that 're-reversal' is detected only for the combination of CCCP with valinomycin raises the possibility that a direct interaction between these ionophores may explain the phenomenon. We show spectroscopic evidence of such an interaction, with a [K+(o)]-dependence similar to that of the 're-reversal.' These data suggest that the reversal of P-glycoprotein activity by valinomycin 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.
|Number of pages||5|
|Journal||Biochemical and biophysical research communications|
|Publication status||Published - Feb 15 1996|
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology