Synergy between two calcium channel blockers, verapamil and fantofarone (SR33557), in reversing chloroquine resistance in Plasmodium falciparum

Abstract

This study describes the synergistic interaction of two calcium channel blockers, verapamil (VR) and SR33557 or fantofarone (SR), in reversing chloroquine resistance in Plasmodium falciparum, the causative agent of human malaria. The two calcium channel blockers exhibited an intrinsic antimalarial activity at 10 and 1 microM for verapamil and fantofarone, respectively. Isobolograms revealed that chloroquine and verapamil, and chloroquine and fantofarone, acted synergistically against chloroquine-resistant strains of P. falciparum. When used at subinhibitory concentrations, verapamil appeared 2 to 3 times more potent than fantofarone in reversing chloroquine resistance. Indeed, verapamil completely reversed the chloroquine resistance in P. falciparum, while fantofarone did so only partially. In the highly chloroquine-resistant strain FcB1, VR and SR acted synergistically to reverse CQ resistance, and the concentrations of VR used in these combinations could be reduced 10- or 100-fold (e.g. 100 nM and 10 nM) those required when this drug was used alone. In the moderately chloroquine-resistant strain K1, a combination of VR and SR for CQ resistance reversal allowed us to reduce the concentration of these chemosensitizers 1000- and 100-fold, respectively. The maximum tolerable plasma level beyond which side-effects occurred when using verapamil is 2.5 microM. Thus, the approach described, which allowed us to lower the doses of chemosensitizers, could well prevent toxic effects in humans and enlighten the advantages of polychemotherapy.