Atorvastatin is a promising partner for antimalarial drugs in treatment of Plasmodium falciparum malaria.
Atorvastatin (AVA) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. AVA exposure resulted in the reduced in vitro growth of 22 Plasmodium falciparum strains, with the 50% inhibitory concentrations (IC(50)s) ranging from 2.5 microM to 10.8 microM. A significant positive correlation was found between the strains' responses to AVA and mefloquine (r = 0.553; P = 0.008). We found no correlation between the responses to AVA and to chloroquine, quinine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, or doxycycline. These data could suggest that the mechanism of AVA uptake and/or the mode of action of AVA is different from those for other antimalarial drugs. The IC(50)s for AVA were unrelated to the occurrence of mutations in the transport protein genes involved in quinoline antimalarial drug resistance, such as the P. falciparum crt, mdr1, mrp, and nhe-1 genes. Therefore, AVA can be ruled out as a substrate for the transport proteins (CRT, Pgh1, and MRP) and is not subject to the pH modification induced by the P. falciparum NHE-1 protein. The absence of in vitro cross-resistance between AVA and chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone, and doxycycline argues that these antimalarial drugs could potentially be paired with AVA as a treatment for malaria. In conclusion, the present observations suggest that AVA is a good candidate for further studies on the use of statins in association with drugs known to have activities against the malaria parasite.
Parquet
Véronique
V
Unité de Recherche en Biologie et Epidémiologie Parasitaires, UMR 6236, Institut de Recherche Biomédicale des Armées, Allée du Médecin-Colonel Jamot, Parc le Pharo, BP 60109, Marseille 13262 Cedex 07, France.
Briolant
Sébastien
S
Torrentino-Madamet
Marylin
M
Henry
Maud
M
Almeras
Lionel
L
Amalvict
Rémy
R
Baret
Eric
E
Fusaï
Thierry
T
Rogier
Christophe
C
Pradines
Bruno
B
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000069059:Atorvastatin; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*
D000962:Antimalarials; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin