Mobile ionophores are a novel class of P‐glycoprotein inhibitors

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Abstract
The decrease of the intracellular concentration of drug in resistant cells compared to sensitive cells is, in most cases, correlated with the presence, in the membrane of resistant cells, of a 170‐kDa P‐glycoprotein responsible for an active efflux of the drug. In an attempt to identify mechanism(s) by which multidrug resistance can be circumvented, we have examined the cellular accumulation of 4′‐O‐tetrahydropyranyl‐adriamycin, alone and in conjunction with various ionophores on the one hand and with cyclosporin A on the other hand. The present study was performed using a spectrofluorometric method with which it is possible to follow continuously the uptake and release of fluorescent molecules by living cells, as the incubation of the cells with the drug proceeds. Erythroleukemia K562 cell lines were used. Using experimental conditions in which these ionophores were unable to modify either the intracellular pH, or the transmembrane potential, or to induce an intracellular ATP depletion, we have shown that mobile ionophores as well as cyclosporin inhibit the P‐glycoprotein‐mediated efflux of 4′‐O‐tetrahydropyranyl‐adriamycin in K562 resistant cells, whereas gramicidin, a channel‐forming ionophore, does not. The concentration that must be used to inhibit 50% of the efflux was 0.7 μM for valinomycin, 0.4 μM for nonactin, 0.2 μM for nigericin, 1.1 μM for monensin, 0.4 μM for lasalocid, 1.2 μM for calcimycin and 0.4 μM for cyclosporin. Due to the high toxicity of the ionophores, the observation that they increased 4′‐O‐tetrahydropyranyl‐adriamycin accumulation in the multidrug‐resistant cells is not correlated with an effect of these compounds on drug resistance. However, the correlation exists in the case of cyclosporin. From our data showing that lipophilic neutral complexes, formed between carboxylic ionophores and metal ions, as well as lipophilic cationic complexes, formed between neutral ionophores and metal ions, are both able to inhibit the P‐glycoprotein‐mediated efflux of anthracycline we can infer that the lipophilicity but not the cationic charge is an important physical property.

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