Circumvention of multidrug-resistance in P388 cells is associated with a rise in the cellular content of phosphatidylcholine.
In fura-2 stained drug-sensitive and multidrug-resistant P388 cells, 50 mM KCl failed to provoke an increase in the fluorescent signal, indicating that potential-dependent Ca2+ channels are not present in either cell line. Therefore the circumvention of drug-resistance by verapamil must be related to some other mechanism. In the present study, verapamil and two other circumventors of drug-resistance, tamoxifen and dipyridamole were found to induce an increase in the synthesis of phosphatidylcholine in multidrug-resistant but not in drug-sensitive cells. The relative resistance of multidrug resistance cells to permeabilization by digitonin indicates that the organization of the plasma membrane lipids in these cells must be different from the one occurring in drug-sensitive cells. Extended exposure of multidrug-resistant cells to verapamil negates the resistance to digitonin. This effect of verapamil reflects its ability to modify the lipid organization of the plasma membrane of multidrug-resistant cells. It is suggested that if the lipid composition of the cell membrane is altered by these drugs as was found for whole cells, the change could explain the increase in drug permeability.
Ramu
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A
Department of Oncology, Hadassah University Hospital, Jerusalem, Israel.
Ramu
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N
Rosario
L M
LM
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002794:Choline / Q000378:metabolism; D004072:Digitonin / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D016257:Fura-2; D015759:Ionomycin / Q000494:pharmacology; D007941:Leukemia P388 / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000302:isolation & purification; D010713:Phosphatidylcholines / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014634:Valinomycin / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*
D008055:Lipids; D010713:Phosphatidylcholines; D013629:Tamoxifen; D014634:Valinomycin; D015759:Ionomycin; D004176:Dipyridamole; D011189:Potassium Chloride; D014700:Verapamil; D004072:Digitonin; D002794:Choline; D016257:Fura-2