This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pradines, B.
Right arrow Articles by Rogier, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pradines, B.
Right arrow Articles by Rogier, C.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, July 2007, p. 2654-2655, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01330-06

LETTERS TO THE EDITOR

Atorvastatin Is 10-Fold More Active In Vitro than Other Statins against Plasmodium falciparum{triangledown}


arrow
LETTER
 
Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, influence a broad array of pathogenic microorganisms. Lovastatin reduces the intracellular growth of Salmonella enterica serovar Typhimurium in cultured macrophages, while atorvastatin does the same in a mouse model (2). Lovastatin additionally reduces the growth of Candida albicans by inhibiting the sterol pathway (11). Statins interfere severely with the growth of protozoan parasites of the Trypanosomatidae family such as Trypanosoma cruzi and various Leishmania species (8, 12, 13). HMG-CoA reductase has been detected in Trypanosoma and Leishmania (3, 8). The presence of an HMG-CoA homolog was not revealed by BLASTX analysis of the Plasmodium falciparum sequence with other protozoal HMG-CoA protein sequences. However, as reported previously, treatment in vitro of Plasmodium falciparum with 120 or 240 µM mevastatin inhibited parasite growth (4, 9).

The susceptibilities to simvastatin, simvastatin sodium salt, pravastatin sodium salt, lovastatin, fluvastatin sodium salt, mevastatin, mevastatin sodium salt (Calbiochem, Merck, Germany), and atorvastatin calcium salt (Molekula, United Kingdom) were assessed in vitro against chloroquine-susceptible P. falciparum strains 3D7 (Africa), D6 (Sierra Leone), and IMT031 (Gabon) and chloroquine-resistant strains W2 (Indochina), Bre1 (Brazil), and FCR3 (The Gambia). Lovastatin and mevastatin were converted to the active form by dissolving the lactone form in 100 µl of 100% ethanol, adding 200 µl of 0.2 M KOH, and then adding 0.2 M HCl for neutralization to pH 7.2 (5). Simvastatin, simvastatin sodium salt, pravastatin sodium salt, lovastatin, fluvastatin sodium salt, mevastatin, mevastatin sodium salt, and atorvastatin calcium salt were dissolved in dimethyl sulfoxide 1% (vol/vol) in RPMI. Twofold serial dilutions, with final concentrations ranging from 1.5 µM to 200 µM, were prepared in dimethyl sulfoxide 1% in RPMI and distributed into Falcon 96-well plates just before use. The isotopic microdrug susceptibility test used was described previously (10).

Table 1 presents the 50% inhibitory concentrations (IC50) of the different statins for P. falciparum. Simvastatin, fluvastatin, lovastatin, and atorvastatin, in the salt active forms, are more active than simvastatin, mevastatin, and lovastatin, in the lactone form. Pravastatin and mevastatin sodium or potassium salts are inactive against P. falciparum (>200 µM). The results indicate that susceptibility to the salts of simvastatin, fluvastatin, lovastatin, and mevastatin is not dependent on the status of chloroquine resistance. The results observed with the simvastatin salt were similar to those reported by other authors (5). Atorvastatin salt, in the range of 5 to 12 µM, is 10-fold more active against P. falciparum than the other salts. Atorvastatin IC90s ranged from 14.8 to 39 µM. The activity of atorvastatin is independent of the status of chloroquine resistance (4.8 to 5.8 µM against chloroquine-resistant strains versus 5.3 to 11.8 µM for the susceptible strains).


View this table:
[in this window]
[in a new window]

  		TABLE 1. In vitro activities of statins against chloroquine-susceptible (3D7, D6, and IMT031) and chloroquine-resistant (W2, Bre1, and FCR3) P. falciparum strains

The chemical structures of simvastatin, lovastatin, mevastatin, and pravastatin are closely related. Those of fluvastatin and atorvastatin are very different from the others. The structural differences between atorvastatin and the other statins could explain differential activity. However, we cannot rule out the action of calcium in the differential activity of atorvastatin.

Multiple daily doses of 2.5 to 80 mg of atorvastatin produced steady-state maximum plasma concentrations of 1.95 to 252 µg liter–1 (in the range of 0.2 to 0.3 µM for the maximum) (1). In L6 cells (rat skeletal muscle cell line), atorvastatin at 100 µM induced death in 27% of the cells (7). Although the atorvastatin IC50 for P. falciparum exceeds these reported plasma concentrations, it may be below toxic concentrations.

Parasites treated with mevastatin show depressed biosynthesis of dolichol and isoprenoid pyrophosphate (4). In addition, mevastatin decreases the viability of cells by inhibiting proteasome activity. Atorvastatin is an inhibitor for phosphoglycoprotein, an efflux protein, and may be a substrate for this transporter as well (6). A phosphoglycoprotein in P. falciparum, Pgh1, is implicated in quinoline resistance.

In conclusion, the present observation suggests that atorvastatin is a good candidate for further studies on the use of statins in malaria treatment.


arrow
ACKNOWLEDGMENTS
 
This work was supported by grant no. 2007rc32 from the Direction Centrale du Service de Santé des Armées.


arrow
FOOTNOTES
 
{triangledown} Published ahead of print on 14 May 2007. Back


arrow
REFERENCES
 
    1
  1. Borek-Dohalsky, V., J. Huclova, B. Barrett, B. Nemec, I. Ulc, and I. Jelinek. 2006. Validated HPLC-MS-MS method for simultaneous determination of atorvastatin and 2-hydroxyatorvastatin in human plasma-pharmacokinetic study. Anal. Bioanal. Chem. 386:275-285.[CrossRef][Medline]
    2. 2
  2. Catron, D. M., Y. Lange, J. Borenztajn, M. D. Sylvester, B. D. Jones, and K. Haldar. 2004. Salmonella enterica serovar Typhimurium requires nonsterol precursors of the cholesterol biosynthetic pathway for intracellular proliferation. Infect. Immun. 72:1036-1042.[Abstract/Free Full Text]
    3. 3
  3. Coppens, I., P. Bastin, T. Levade, and P. J. Courtoy. 1995. Activity, pharmacological inhibition and biological regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in Trypanosoma brucei. Mol. Biochem. Parasitol. 69:29-40.[CrossRef][Medline]
    4. 4
  4. Couto, A. S., E. A. Kimura, V. J. Peres, M. L. Uhrig, and A. M. Katzin. 1999. Active isoprenoid pathway in the intra-erythrocytic stages of Plasmodium falciparum: presence of dolichols of 11 and 12 isoprene units. Biochem. J. 341:629-637.[CrossRef][Medline]
    5. 5
  5. Grellier, P., A. Valentin, V. Millerioux, J. Schrevel, and D. Rigomier. 1994. 3-Hydroxy-methylglutaryl coenzyme A reductase inhibitors lovastatin and simvastatin inhibit in vitro development of Plasmodium falciparum and Babesia divergens in human erythrocytes. Antimicrob. Agents Chemother. 38:1144-1148.[Abstract/Free Full Text]
    6. 6
  6. Holtzman, C. W., B. S. Wiggings, and S. A. Spinler. 2006. Role of P-glycoprotein in statin drug interaction. Pharmacotherapy 26:1601-1607.[CrossRef][Medline]
    7. 7
  7. Kaufmann, P., M. Torok, A. Zahno, K. M. Walhauser, K. Brecht, and S. Krahenbuhl. 2006. Toxicity of statins on rat skeletal muscle mitochondria. Cell. Mol. Life Sci. 63:2415-2425.[CrossRef][Medline]
    8. 8
  8. Montalvetti, A., J. Pana-Diaz, R. Hurtado, L. M. Ruiz-Perez, and D. Gonzalez-Pacanowska. 2000. Characterization and regulation of Leishmania major 3-hydroxy-methyl-glutaryl-CoA reductase. Biochem. J. 349:27-34.[CrossRef][Medline]
    9. 9
  9. Naik, R. S., M. Venkatesan, and D. C. Gowda. 2001. Plasmodium falciparum: the lethal effects of tunicamycin and mevastatin on the parasite are not mediated by inhibition of N-linked oligosaccharide biosynthesis. Exp. Parasitol. 98:110-114.[CrossRef][Medline]
    10. 10
  10. Pradines, B., J. M. Rolain, F. Ramiandrasoa, T. Fusai, J. Mosnier, C. Rogier, W. Daries, E. Baret, G. Kunesch, J. Le Bras, and D. Parzy. 2002. Iron chelators as antimalarial agents: in vitro activity of dicatecholate against Plasmodium falciparum. J. Antimicrob. Chemother. 50:177-187.[Abstract/Free Full Text]
    11. 11
  11. Song, J. L., C. N. Lyons, S. Holleman, B. G. Oliver, and T. C. White. 2003. Antifungal activity of fluconazole in combination with lovastatin and their effects on gene expression in the ergosterol and prenylation pathways in Candida albicans. Med. Mycol. 41:417-425.[CrossRef][Medline]
    12. 12
  12. Urbina, J. A., K. Lazardi, E. Marchan, G. Visbal, T. Aguirre, M. M. Piras, R. Piras, R. A. Maldonado, G. Payares, and W. de Souza. 1993. Mevinolin (lovastatin) potentiates the antiproliferative effects of ketoconazole and terbinafine against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies. Antimicrob. Agents Chemother. 37:580-591.[Abstract/Free Full Text]
    13. 13
  13. Yokoyama, K., P. Trobridge, F. S. Buckner, J. Scholten, K. D. Stuart, W. C. van Voorhis, and M. H. Gelb. 1998. The effects of protein farnesyltransferase inhibitors on trypanosomatids: inhibition of protein farnesylation and cell growth. Mol. Biochem. Parasitol. 94:87-97.[CrossRef][Medline]
Bruno Pradines*
Unité de Recherche en Biologie et Epidémiologie Parasitaires
Institut de Médecine Tropicale du Service de Santé des Armées
Le Pharo
13998 Marseille, France

Marylin Torrentino-Madamet
Unité de Recherche en Pharmacologie et Physiopathologie Parasitaires
Institut de Médecine Tropicale du Service de Santé des Armées
Le Pharo
13998 Marseille, France

Albin Fontaine
Maud Henry
Eric Baret
Joel Mosnier
Sébastien Briolant
Thierry Fusai
Christophe Rogier
Unité de Recherche en Biologie et Epidémiologie Parasitaires
Institut de Médecine Tropicale du Service de Santé des Armées
Le Pharo
13998 Marseille, France

* Phone: 33 4 91 15 01 10, Fax: 33 4 91 15 01 64, E-mail: bruno.pradines{at}free.fr

Antimicrobial Agents and Chemotherapy, July 2007, p. 2654-2655, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01330-06




This article has been cited by other articles:

  • Parquet, V., Briolant, S., Torrentino-Madamet, M., Henry, M., Almeras, L., Amalvict, R., Baret, E., Fusai, T., Rogier, C., Pradines, B. (2009). Atorvastatin Is a Promising Partner for Antimalarial Drugs in Treatment of Plasmodium falciparum Malaria. Antimicrob. Agents Chemother. 53: 2248-2252 [Abstract] [Full Text]  
  • Wong, R. P. M., Davis, T. M. E. (2009). Statins as Potential Antimalarial Drugs: Low Relative Potency and Lack of Synergy with Conventional Antimalarial Drugs. Antimicrob. Agents Chemother. 53: 2212-2214 [Abstract] [Full Text]  
  • Bienvenu, A.-L., Picot, S. (2008). Statins Alone Are Ineffective in Cerebral Malaria but Potentiate Artesunate. Antimicrob. Agents Chemother. 52: 4203-4204 [Full Text]  
  • Kobbe, R., Schreiber, N., May, J., Jacobs, T. (2008). Simvastatin Treatment Shows No Effect on the Incidence of Cerebral Malaria or Parasitemia during Experimental Malaria. Antimicrob. Agents Chemother. 52: 1583-1584 [Full Text]  

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pradines, B.
Right arrow Articles by Rogier, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pradines, B.
Right arrow Articles by Rogier, C.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»