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Antimicrobial Agents and Chemotherapy, June 2009, p. 2248-2252, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01462-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Atorvastatin Is a Promising Partner for Antimalarial Drugs in Treatment of Plasmodium falciparum Malaria{triangledown}

Véronique Parquet,1 Sébastien Briolant,1 Marylin Torrentino-Madamet,2 Maud Henry,1 Lionel Almeras,1 Rémy Amalvict,1 Eric Baret,1 Thierry Fusaï,1 Christophe Rogier,1 and Bruno Pradines1*

Unité de Recherche en Biologie et Epidémiologie Parasitaires, Unité de Recherche pour les Maladies Infectieuses et Tropicales Emergentes, UMR 6236, Institut de Recherche Biomédicale des Armées, Institut de Médecine Tropicale du Service de Santé des Armées, Marseille, France,1 Unité de Recherche en Physiologie et Pharmacocinétique Parasitaires, UMR-MD3 Relations Hôte-Parasites, Pharmacologie et Thérapeutique, Institut de Médecine Tropicale du Service de Santé des Armées, Marseille, France2

Received 2 November 2008/ Returned for modification 24 January 2009/ Accepted 14 March 2009


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ABSTRACT
 
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 (IC50s) ranging from 2.5 µM to 10.8 µM. 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 IC50s 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.


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INTRODUCTION
 
During the past 20 years, many strains of Plasmodium falciparum have become resistant to chloroquine and other antimalarial drugs (20). This has prompted a search for an effective alternative antimalarial drug with minimal side effects. The emergence and spread of parasites resistant to antimalarial drugs have caused an urgent need for the discovery and development of novel compounds.

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. They comprise a family of lipid-lowering drugs that are currently used to control hyperlipidemia and are considered useful for the prevention of cardiovascular events. Apart from the cholesterol-lowering activities of statins, their immunomodulation and pleiotropic effects may significantly affect infection-related survival (13, 28). There is increasing evidence that statins may be useful for the prevention and treatment of infections (11). Lovastatin reduced the intracellular growth of Salmonella enterica serovar Typhimurium in cultured macrophages, as did atorvastatin (AVA) in a mouse model (5). Lovastatin also reduced the level of in vitro infection due to Coxiella burnetii (4) and additionally reduced the growth of Candida albicans by inhibiting the sterol pathway (27).

Statins were found to interfere severely with the growth of protozoan parasites of the family Trypanosomatidae, such as Trypanosoma cruzi, and various Leishmania species (32). HMG-CoA reductase has been detected in Trypanosoma and Leishmania (7).

Furthermore, statins have been shown to have in vitro antimalarial activities, even though the presence of an HMG-CoA sequence homologous with other protozoal HMG-CoA protein sequences was not revealed by a BLASTX analysis of the P. falciparum sequence. The in vitro exposure of P. falciparum to 120 or 240 µM mevastatin inhibited parasite growth (8, 24). Lovastatin was reported to reduce the in vitro growth of P. falciparum (14). AVA was found to be 10-fold more active against six P. falciparum strains than other statins when it was applied at concentrations that ranged from 5 to 12 µM (26).

In patients with cardiovascular risk factors and chronic kidney disease, preventative treatment with statins reduced the incidence of sepsis. In experimental models of sepsis, simvastatin prolonged the survival time of mice. Statins have been demonstrated to have effects against severe sepsis (28). These conditions share common physiopathological features, especially with regard to the pathology of the endothelium. Indeed, severe malaria is a type of severe sepsis. Statins such as lovastatin have been shown to exert their effects on blood platelets (22), which interfere with cerebral malaria (6), and AVA was found to play a pleiotropic role, such as reducing the level of inflammation (28). A number of works have provided data supporting the roles of immune status, the inflammatory response, and the genetic background of the host in the development of malaria.

AVA may be a substrate for phosphoglycoprotein (Pgp), an efflux protein in cancer cells (17, 31). Several antimalarial drugs, e.g., the quinolines, were shown to be substrates for the multidrug resistance (MDR)-like proteins involved in P. falciparum: Pgh1 or P. falciparum multidrug resistance protein 1 (PfMDR1) and the P. falciparum MDR protein (PfMRP) (15, 25).

The objectives of this study were to (i) assess the in vitro activity of AVA against 22 strains of P. falciparum from a large number of countries and with different susceptibility profiles; (ii) evaluate the in vitro cross-resistance of AVA with chloroquine (CQ), quinine (QN), monodesethylamodiaquine (MDAQ), mefloquine (MQ), lumefantrine (LMF), dihydroartemisinin (DHA), atovaquone (ATV), and doxycycline (DOX); and (iii) determine whether AVA could be a substrate for P. falciparum MDR-like proteins, such as Pgh1 and PfMRP, or transporters involved in drug resistance, such as the P. falciparum CQ resistance transporter (PfCRT) and the P. falciparum sodium-hydrogen exchanger (PfNHE-1), by the identification of genetic polymorphisms.


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MATERIALS AND METHODS
 
Plasmodium falciparum cultures. In total, 22 parasite strains (familiar laboratory strains or strains obtained from isolates after growth in culture for an extended period of time) from a large number of countries or regions (Brazil, Cambodia, Cameroon, Djibouti, French Guyana, The Gambia, Honduras, Indochina, Niger, Republic of Comoros, Republic of the Congo, Senegal, Sierra Leone, Sudan, Thailand, and Uganda) were maintained in culture in RPMI 1640 medium (Invitrogen, Paisley, United Kingdom) supplemented with 10% human serum (Abcys S.A., Paris, France) and buffered with 25 mM HEPES-25 mM NaHCO3. The parasites were grown in type A-positive human blood under controlled atmospheric conditions that consisted of 10% O2, 5% CO2, and 85% N2 at 37°C with 95% humidity. All strains were twice synchronized with sorbitol before use (19). The susceptibility of each strain to antimalarial drugs was assessed in at least 4 independent experiments and in some cases up to 23 independent experiments. Clonality was verified by genotyping by PCR of the polymorphic genetic markers msp1, msp2, and microsatellite loci (3, 16). These strains showed different chemosusceptibility profiles: 11 were resistant to CQ (i.e., 50% inhibitory concentrations [IC50s], >100 nM); 2 had reduced susceptibility to QN (IC50s, >800 nM); 16 had reduced susceptibility to MQ (IC50s, >30 nM); 10 had reduced susceptibility to MDAQ (IC50s, > 80 nM); and none had reduced susceptibility to LMF, DHA, ATV, or DOX.

Drugs. The AVA calcium salt was purchased from Molekula (United Kingdom). CQ, QN, DHA, and DOX were purchased from Sigma (St. Louis, MO). MDAQ was obtained from the World Health Organization (Geneva, Switzerland), MQ was from Hoffmann-La Roche (Basel, Switzerland), LMF was from Novartis Pharma (Basel, Switzerland), and ATV was from GlaxoSmithKline (Evreux, France). AVA was dissolved in 1% (vol/vol) dimethyl sulfoxide in RPMI 1640 medium. Twofold serial dilutions with final concentrations ranging from 0.15 µM to 200 µM were prepared in RPMI 1640 medium-1% dimethyl sulfoxide and distributed into Falcon 96-well plates just before use. CQ was resuspended and diluted in water at concentrations ranging from 5 to 3,200 nM. QN, MDAQ, MQ, DHA, ATV, and DOX were first dissolved in methanol and were then diluted in water to obtain final concentrations ranging from 5 to 3,200 nM for QN, 1.56 to 1,000 nM for MDAQ, 3.2 to 400 nM for MQ, 0.1 to 100 nM for DHA, 0.3 to 100 nM for ATV, and 0.1 to 502 µM for DOX. LMF was resuspended and diluted in ethanol to obtain final concentrations ranging from 0.5 to 310 nM.

In vitro assay. For in vitro isotopic microtests, 25 µl/well of antimalarial drug and 200 µl/well of the suspension of synchronous parasitized red blood cells (final parasitemia, 0.5%; final hematocrit, 1.5%) were distributed in 96-well plates. Parasite growth was assessed by adding 1 µCi of tritiated hypoxanthine with a specific activity of 14.1 Ci/mmol (Perkin-Elmer, Courtaboeuf, France) to each well at time zero. The plates were then incubated for 48 h under controlled atmospheric conditions. Immediately after incubation, the plates were frozen and then thawed in order to lyse the erythrocytes. The content of each well was collected on standard filter microplates (Unifilter GF/B; Perkin-Elmer) and was washed with a cell harvester (Filter-Mate; Perkin-Elmer). The filter microplates were dried, and 25 µl of scintillation cocktail (Microscint O; Perkin-Elmer) was placed in each well. The radioactivity incorporated into the nucleotides by the parasites was measured with a scintillation counter (Top Count; Perkin-Elmer).

The drug IC50 for parasite growth was assessed by determining the concentration at which 50% of the tritiated hypoxanthine had been incorporated by the parasite in the drug-free control wells. The IC50 was calculated by nonlinear regression analysis of log-based dose-response curves (Riasmart; Packard, Meriden, CT).

Nucleic acid extraction. Total genomic DNA from each strain was isolated by an extraction method with an EZNA blood DNA kit (Omega Bio-Tek). The RNA from each strain was purified with a QIAamp blood minikit (Qiagen, Hilden, Germany).

Pfcrt single-nucleotide polymorphisms (SNPs). A 1,250-nucleotide length fragment of the Pfcrt gene was amplified with primers F1-sense (5'-TAA TTT CTT ACA TAT AAC AAA ATG AAA TTC-3') and F1-antisense (5'-TTA TTG TGT AAT AAT TGA ATC GAC-3') and was sequenced with primers F2-sense (5'-TAG GTG GAG GTT CTT GTC TTG GTA-3') and F2-antisense (5'-TCG ACG TTG GTT AAT TCT CCT TC-3'), as described previously (10). Amplifications were performed by using the conditions recommended in the Access reverse transcription-PCR system kit (Promega, Madison, WI). Sequencing was conducted with ABI Prism BigDye Terminator (version 1.1) cycle sequencing ready reaction kits, according to the instructions of the manufacturer (Applied Biosystems).

Pfmdr1 SNPs. Pfmdr1 was amplified by PCR with the following primer pairs: 5'-TTA CAT TTT ATT TGA TTT TGT GTT G-3' and 5'-CAT CTT TTC TAG TAT CAT AAT GAA-3' to amplify codons 86 and 184 and 5'-ACG GGT TTA GTA AAT AAT ATT GTT-3' and 5'-ATG GGT TCT TGA CTA ACT ATT G-3' to amplify codons 1034, 1042, and 1246. Amplifications were performed with a Titanium PCR kit (Clontech Ozyme, France), according to the manufacturer's instructions. The amplified fragments were sequenced as described above.

Pfmrp SNPs. PCR amplification followed by sequencing was used to detect SNPs in Pfmrp at positions 191 and 437. The primers used for amplification and sequencing were Pfmrp-501F (5'-TTT CAA AGT ATT CAG TGG GT-3') and Pfmrp-1409R (5'-GGC ATA ATA ATT GAT GTA AA-3').

Pfnhe-1 microsatellite profiles. A sequence containing the previously described ms4760 microsatellite (12) was amplified with primers pfnhe-3802F (5'-TTATTAAATGAATATAAAGA-3') and pfnhe-4322R (5'-TTTTTTATCATTACTAAAGA-3'). The amplified fragments were sequenced as described above.

Statistical analysis. The effect of AVA on the IC50 was tested by the Kruskal-Wallis test. Assessment of the cross-resistance of standard antimalarial drugs with AVA was estimated by determination of the coefficient of correlation (r) and the coefficient of determination (r2). The Kruskal-Wallis test or the Mann-Whitney U test was used, when appropriate, to compare the equality of populations for each mutation. To account for multiple comparisons, the results of these tests were considered statistically significant only when the value of P was <0.0026 (0.05 divided by the number of tests, which was 19) by application of the Bonferroni correction.


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RESULTS
 
The in vitro activity of AVA against 22 synchronized P. falciparum strains was evaluated and compared to the activities of CQ, QN, MQ, MDAQ, LMF, DHA, ATV, and DOX.

The mean IC50s (4 to 23 experiments per strain) ranged from 2.5 µM to 10.8 µM (Fig. 1). A significant difference was found between the AVA IC50 for the 22 P. falciparum strains (Kruskal-Wallis, P = 0.0001). The mean IC50s ranged from 25 to 665 nM for CQ, 48 to 969 nM for QN, 14 to 65 nM for MQ, 23 to 314 nM for MDAQ, 8 to 42 nM for LMF, 0.9 to 5.8 nM for DHA, 2.4 to 9.5 nM for ATV, and 8.4 to 14.9 µM for DOX.


Figure 1
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  		FIG. 1. Distribution of IC50s for 22 Plasmodium falciparum strains. Mean IC50, 7.7 µM; 95% confidence interval, 6.5 to 8.2 µM.

The correlations between the in vitro responses of the 22 P. falciparum strains to AVA and their responses to the other antimalarial drugs are presented in Table 1. A significant positive correlation between the responses to AVA and MQ was found (r = 0.553; P = 0.008). No significant correlation between the AVA IC50 and the responses to the other antimalarial drugs was shown.


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  		TABLE 1. Correlation of the in vitro responses of 22 strains of Plasmodium falciparum to AVA, CQ, QN, MQ, MDAQ, LMF, DHA, ATV, and DOX

The following mutations were identified in at least one strain: Pfcrt M74I, N75E, K76T, A220S, Q271(E/V), N326S, I356T, and I371R; Pfmrp H191Y and S437A; and Pfmdr1 N86Y, Y184F, S1034C, N1042D, and D1246Y (Table 2). Seven different ms4760 microsatellite profiles for Pfnhe-1 were observed. The number of DNNND and DDNHNDNHNN repeats in ms4760 ranged from one to four and one to two, respectively. We did not find a significant association between the AVA IC50 and polymorphisms in the Pfcrt, Pfmdr1, Pfmrp, and Pfnhe-1 genes (0.2412 < P < 0.9373). Significant associations were shown between the responses to CQ, MDAQ, QN, and MQ and polymorphisms in the Pfcrt gene. An association was also found between the responses to MDAQ and QN and polymorphisms in the Pfmrp gene (Table 3).


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  		TABLE 2. Pfcrt, Pfmdr1, Pfmrp, and Pfnhe-1 polymorphisms in 22 Plasmodium falciparum strains


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  		TABLE 3. Association between the in vitro responses (IC50s) to AVA, CQ, MDAQ, QN, and MQ and polymorphisms in the Pfnhe-1, Pfcrt, Pfmdr1, and Pfmrp genes of 22 Plasmodium falciparum strains


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DISCUSSION
 
AVA is an HMG-CoA reductase inhibitor that reduces the in vitro growth of P. falciparum. The in vitro activity of AVA is in the low micromolar range. The mean AVA IC50 for the different strains ranged from 2.5 µM to 10.8 µM. A generally agreed upon level of efficacy would be in the low or middle nanomolar range. However, if the mechanisms of action of such a compound are sufficiently novel and different from those of the commonly used antimalarial drugs, this compound could warrant further study. The mechanisms of action of AVA seem to be different from those of commonly used antimalarial drugs. A positive correlation between the IC50s of two antimalarial drugs may suggest in vitro cross-resistance or at least a common mechanism of action. However, the relationship between in vitro resistance and in vivo resistance depends on the level of resistance and the values of r and r2. In order for two compounds to utilize the same mechanism of action or resistance, which could induce cross-resistance, the r2 value must be high, such as that for CQ and MDAQ (r2 = 0.8712) or CQ and QN (r2 = 0.7628). Eighty-seven percent and 76% of the variation among the responses to CQ can be explained by variations in the responses to MDAQ and QN. These three antimalarial drugs act by inhibiting heme crystallization. The r2 values calculated for the responses to AVA and CQ, QN, MDAQ, DHA, ATV, and DOX were less than 0.10; those for MQ and LMF were 0.31 and 0.21, respectively. This suggests that less than 10% of the variation among the responses to AVA can be explained by variations in the responses to the other drugs. Twenty-one percent and 31% of the variation among the responses to AVA can be explained by variations in the responses to LMF and MQ, respectively. These data for LMF and MQ, which are too weak to predict cross-resistance, could suggest that AVA could be partially associated with Pgh1, like LMF and MQ are (9, 21). However, these data could suggest a different mode of drug uptake and/or a different mode of action for AVA and the other compounds (no interaction with heme crystallization or cytochrome b). These data are consistent with the lack of a significant association between the AVA responses (IC50) and polymorphisms in genes involved in quinoline resistance, such as Pfcrt for CQ and MDAQ (29), Pfmdr1 for MQ (21) and LMF (9), Pfnhe-1 for QN, and Pfmrp for CQ and QN (23, 30). The IC50s for AVA were found to be unrelated to mutations in the genes for transport proteins involved in quinoline antimalarial drug resistance. Therefore, AVA cannot be considered a substrate for these transport proteins (PfCRT, Pgh1, and PfMRP) or to be subject to the pH modification induced by PfNHE-1. DNNND repeat polymorphisms might alter the regulation of PfNHE and induce pH perturbations (1). These data suggest that AVA may not be expelled by the transport proteins involved in quinoline resistance in P. falciparum parasites. Our findings are different from the data reported for human Pgp (17), which considered AVA to be a moderate Pgp substrate. However, to conclude that an interaction between AVA and Pgh1 is absent, the association of the number of copies of Pfmdr1 and susceptibility to AVA should be evaluated in studies with more isolates.

The unique mechanism of drug uptake and/or mode of action for AVA and the other antimalarial drugs tested in the present study makes it a good candidate for the treatment of malaria. AVA is an HMG-CoA reductase inhibitor. Nevertheless, the presence of an HMG-CoA homolog was not revealed by BLASTX analysis of the P. falciparum HMG-CoA sequence and other protozoal HMG-CoA protein sequences. Parasites treated with mevastatin show depressed levels of biosynthesis of dolichol and isoprenoid pyrophosphate (8). In addition, mevastatin decreases the viability of cells by inhibiting proteasome activity. One of our objectives in future studies will be to identify modifications of the P. falciparum proteome in parasites exposed to AVA.

Simvastatin, pravastatin, fluvastatin, or AVA used alone at doses ranging from 20 to 100 mg/kg of body weight failed to prevent death from cerebral malaria. Furthermore, these doses showed no effect on the level of parasitemia in infected mice (2, 18). It could be speculated that AVA may act as an adjuvant therapy. AVA seemed to potentiate the activity of artesunate, since one report found that AVA was able to prevent death from cerebral malaria and reduce the level of parasitemia in infected mice when it was used in combination with artesunate (2). The absence of in vitro cross-resistance between AVA and CQ, QN, MQ, MDAQ, LMF, DHA, ATV, or DOX suggests that all of these antimalarial drugs could potentially be good partners for AVA.

In conclusion, the present observations suggest that AVA should be considered a good drug to be used together with known antimalarials.


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ACKNOWLEDGMENTS
 
This work was supported by the Direction Centrale du Service de Santé des Armées (grant no. 2007 RC 32).

We have no conflicts of interest concerning the work reported in this paper. We do not own stocks or shares in a company that might be financially affected by the conclusions of this article. The conclusion of this article was not financially influenced.


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FOOTNOTES
 
* Corresponding author. Mailing address: Unité de Recherche en Biologie et Épidémiologie Parasitaires, Institut de Recherche Biomédicale des Armées, Institut de Médecine Tropicale du Service de Santé des Armées, Allée du Médecin-Colonel Jamot, Parc le Pharo, BP 60109, Marseille 13262 Cedex 07, France. Phone: 33 4 91 15 01 10. Fax: 33 4 91 15 01 64. E-mail: bruno.pradines{at}free.fr Back

{triangledown} Published ahead of print on 13 March 2009. Back


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Antimicrobial Agents and Chemotherapy, June 2009, p. 2248-2252, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01462-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Savini, H., Souraud, J. B., Briolant, S., Baret, E., Amalvict, R., Rogier, C., Pradines, B. (2010). Atorvastatin as a Potential Antimalarial Drug: In Vitro Synergy in Combinational Therapy with Dihydroartemisinin. Antimicrob. Agents Chemother. 54: 966-967 [Full Text]  

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