Reversal of Chloroquine Resistance in Plasmodium falciparum by Verapamil

Abstract

The parasite Plasmodium falciparum, like neoplastic cells, develops resistance to multiple structurally unrelated drugs. If the mechanisms by which P. falciparum and neoplastic cells become resistant are similar, then it may be possible to reverse the resistance in the two types of cells by the same pharmacological agents. Verapamil, a calcium channel blocker, completely reversed chloroquine resistance in two chloroquine-resistant P. falciparum clones from Southeast Asia and Brazil. Verapamil reversed chloroquine resistance at the same concentration (1 X 10(-6)M) as that at which it reversed resistance in multidrug-resistant cultured neoplastic cells. This same concentration of verapamil had no effect on chloroquine-sensitive parasites. Hence, chloroquine resistance in P. falciparum may fit the criteria for the multidrug-resistant phenotype.

Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials

“…Chloroquine resistance is thought to arise, at least in part, from a decreased level of chloroquine uptake, although some studies suggest that an alteration in the drug target may also be involved [30,36,45]. Chloroquine resistance can be reversed in itro and in animal models by co-administration of compounds such as verapamil, chlorpromazine and desipramine [46][47][48]. These reagents have been shown to enhance chloroquine uptake by chloroquineresistant parasites, although recent work has shown that the apparent reversal of chloroquine resistance by these drugs cannot entirely be accounted for by an increase in chloroquine accumulation [49,50].…”

“…Indeed, drugs such as chlorpromazine and verapamil are known to be toxic to malaria parasites, albeit at relatively high concentrations (i.e., several µM) [46,48,52]. These weakly basic, hydrophobic drugs will be accumulated much less efficiently than chloroquine [36], but at higher external concentrations may reach sufficiently high levels in the food vacuole to exert an effect on haem breakdown.…”

Chloroquine-resistant isoforms of the Plasmodium falciparum chloroquine resistance transporter acidify lysosomal pH in HEK293 cells more than chloroquine-sensitive isoforms

“…For example, while verapamil, a calcium channel antagonist, reverses CQ resistance [21], the mechanism of reversal is uncertain, despite evidence that PfCRT is involved [5,10,20]. Physiological and biochemical studies of Plasmodium proteins in situ are time consuming and subject to technical barriers [22].…”

Isradipine – a calcium channel blocker – does not potentiate chloroquine antiplasmodial activity againstPlasmodium falciparum

“…concentrations ranged from 2 to 200 µM. The effect of isradipine on the activities of the antimalarials was determined by combination test (Martin et al, 1987). The chloroquine-resistant strain P. falciparum FCM29 maintained in continuous culture was also tested immediately after synchronization using the sorbitol-based method (Lambros & Vanderberg, 1979).…”

“…An isobologram close to the diagonal indicates an additive effect. Curves significantly above or below the diagonal indicate antagonistic or synergistic effects, respectively (Berenbaum, 1978;Martin et al, 1987).…”