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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 resistant 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.

Multidrug-resistant P388 cells were found to be resistant also to a variety of ammonium, phosphonium and arsonium compounds. As previously shown for anthracyclines and vinca alkaloids, the resistance to the permanently charged lipophilic cationic compounds could be circumvented by verapamil. Relative to drug-sensitive cells, K + uptake and plasma membrane Mg-ATPase activity in multidrug-resistant cells are ouabain resistant. The intracellular K + concentration in drug-resistant cells is maintained at a normal level by increased activity of the furosemide sensitive transport system. It is suggested that the reduced activity of the electrogenic Na + -K + pump in multidrug-resistant, cells could result in a lower transmembrane potential and therefore reduced accumulation of cationic lipophilic compounds.