The effect of mefloquine and volume-regulated anion channel inhibitors on induced transport in Plasmodium falciparum-infected human red blood cells

The malaria parasite Plasmodium falciparum activates new permeation pathways (NPP) in the host cell membrane of infected human red blood cells (RBCs), which are permeable to anions, cations and a range of organic solutes. It has been suggested from inhibitor and substrate selectivity studies that the NPP may be identical to the volume-activated anion channel (VRAC) present in many mammalian cell types. Here we have tested several known inhibitors of VRAC on the transport of choline and lactate in malaria-infected human RBCs and on parasite growth. Mefloquine, tamoxifen and clomiphene were all without effect on malaria-induced transport at concentrations up to 10 μM and only mefloquine (IC50 = 24 nM) and, to a lesser degree, clomiphene (IC50 = 6.2 μM) inhibited parasite growth below this level. It is concluded that the antimalarial effect of mefloquine does not involve the inhibition of malaria-induced transport via the NPP and there is no evidence at present for VRAC and the NPP being identical.