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.