Entamoeba histolytica: Physiology of multidrug resistance

Abstract

Crossresistance to unrelated drugs has been previously observed in multidrug-resistant carcinoma cells and the goal of this work was to determine whether a similar mechanism existed in Entamoeba histolytica. An emetine and a colchicine-resistant clone, C2(90) (IC 50 = 62 μ M, and 1.5 m M, respectively), and the parental clone, A (IC 50 = 5 μ M and 1 m M, respectively), were analyzed for resistance to other drugs and for the effect of verapamil. Both clones, C2(90) and A, exhibited similar resistance to both daunomycin (IC 50 = 50 μ M) and actinomycin D (IC 50 = 13 n M). In the presence of verapamil, the IC 50 for emetine was reduced to 0.5 μ M, while the IC 50 for colchicine was reduced to 0.3 m M. These results demonstrate that verapamil reverses both emetine and colchicine resistance in the mutant C2(90). In uptake experiments with [ 3H]emetine, drug accumulation was lower in resistant trophozoites. However, in the presence of verapamil, drug accumulation was increased in clone C2(90) to a level close to that of the parental strain, clone A. These results are consistent with observations made using malaria and multidrug-resistant tumor cells and suggest that a P-glycoprotein-like molecule may play a role in drug resistance in E. histolytica.