Synergy between verapamil and other multidrug -resistance modulators in model membranes

Abstract

Various cationic lipophilic compounds can reverse the multidrug resistance of cancer cells. Possible interaction between these compounds, which are known as modulators, has been assessed by measuring leakage of Sulphan blue from anionic liposomes, induced both by verapamil alone and by verapamil in combination with diltiazem, quinine, thioridazine or clomipramine. An equation was derived to quantify the permeation doses and Hill coefficients of the drugs and mixtures between them by simultaneous fitting of the experimental data. The interaction was tested by two methods, the competition plot and the isobole method; both showed synergy between verapamil and each of diltiazem, quinine and thioridazine. The dose factor of potentiation for verapamil determined within membranes was 4.0 +/- 0.4 with diltiazem, 3.2 +/-0.4 with quinine and 2.4 +/- 0.3 with thioridazine. The results suggest that the effectiveness of reversing multidrug resistance may be increased with modulators such as verapamil and diltiazem that have a much greater effect in combination than what would be expected from their effects when considered separately.