Alterations of ionic membrane permeabilities in multidrug-resistant neuroblastoma x glioma hybrid cells.
A population of NG108-15 neuroblastoma cells resistant to doxorubicin (NG/DOXR) was established. The cells exhibited a multidrug resistance phenotype with cross-resistance to vinblastin and colchicine, overexpression of a 170 kDa membrane protein identified as P-glycoprotein and reversal of resistance by verapamil and quinine. Compared with NG108-15 cells, NG/DOXR cells showed an increase in Na+ current density and a decrease in cyclic-AMP-activated Cl- current density with no change in K+- and volume-sensitive Cl- current densities. As previously observed in NG108-15 cells, the vacuolar-type H+-ATPase inhibitors bafilomycin A1 and nitrate induced membrane depolarizations in NG/DOXR cells. The resting potentials of sensitive and resistant cells were not significantly different, but the depolarizations evoked by these agents were significantly larger in NG/DOXR than in NG108-15 cells. The resting membrane potential of NG/DOXR cells, but not that of NG108-15 cells, was depolarized by verapamil, and this effect was abolished by bafilomycin. The volume-sensitive Cl- currents of drug-sensitive and drug-resistant cells were inhibited by a decrease in intracellular pH from 7.3 to 6.8. Whereas bafilomycin prevents activation of Cl- currents in both drug-sensitive and drug-resistant cells, verapamil inhibited the Cl- current only in NG/DOXR cells. The results are discussed in terms of the roles of cytoplasmic pH and membrane potential in multidrug resistance.
Gérard
V
V
Laboratoire de Neurobiologie cellulaire et moléculaire, CNRS, 91198 Gif-sur-Yvette Cedex, France.
Rouzaire-Dubois
B
B
Dilda
P
P
Dubois
J M
JM
D000818:Animals; D000970:Antineoplastic Agents; D002454:Cell Differentiation; D002463:Cell Membrane Permeability; D048429:Cell Size; D018118:Chloride Channels / Q000502:physiology; D004317:Doxorubicin; D018432:Drug Resistance, Multiple; D004553:Electric Conductivity; D005910:Glioma / Q000648:ultrastructure*; D006825:Hybridomas / Q000648:ultrastructure*; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials; D051379:Mice; D009447:Neuroblastoma / Q000648:ultrastructure*; D017494:Proton Pumps; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D015222:Sodium Channels / Q000502:physiology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D000970:Antineoplastic Agents; D018118:Chloride Channels; D017494:Proton Pumps; D015222:Sodium Channels; D004317:Doxorubicin; D011803:Quinine; D014700:Verapamil