Reversal of multidrug resistance by valinomycin is overcome by CCCP.
Reversal of P-glycoprotein-mediated multidrug resistance by valinomycin is overcome by the 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+(0)]) dependence. It is observed at [K+(0)] > 2-4 mM and not at [K+(0)] greater than or equal to 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+(0)]-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.
Goda
K
K
Department of Biophysics, University Medical School of Debrecen, Hungary.
Krasznai
Z
Z
Gaspar
R
R
Lankelma
J
J
Westerhoff
H V
HV
Damjanovich
S
S
Szabó
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D004396:Coloring Agents / Q000378:metabolism; D003630:Daunorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007624:KB Cells; D007700:Kinetics; D011188:Potassium / Q000494:pharmacology; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D014634:Valinomycin / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004396:Coloring Agents; D007476:Ionophores; D012235:Rhodamines; D020112:Rhodamine 123; D014634:Valinomycin; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D014747:Vinblastine; D011188:Potassium; D003630:Daunorubicin