Skip to main content Accessibility help
×
Home

Anti-Trypanosoma cruzi effects of cyclosporin A derivatives: possible role of a P-glycoprotein and parasite cyclophilins

  • J. BÚA (a1), L. E. FICHERA (a1), A. G. FUCHS (a2) (a3), M. POTENZA (a1), M. DUBIN (a2), R. O. WENGER (a4), G. MORETTI (a1), C. M. SCABONE (a1) and A. M. RUIZ (a1)...

Summary

Cyclophilins are target molecules for cyclosporin A (CsA), an immunosuppressive antimicrobial drug. We have previously reported the in vitro anti-Trypanosoma cruzi activity of H-7-94 and F-7-62 non-immunosuppressive CsA analogues. In this work, we continue the study of the parasiticidal effect of H-7-94 and F-7-62 CsA analogues in vitro and in vivo and we analyse 3 new CsA derivatives: MeIle-4-CsA (NIM 811), MeVal-4-CsA (MeVal-4) and D-MeAla-3-EtVal-4-CsA, (EtVal-4). The most efficient anti-T. cruzi effect was observed with H-7-94, F-7-62 and MeVal-4 CsA analogues evidenced as inhibition of epimastigote proliferation, trypomastigote penetration, intracellular amastigote development and in vivo T. cruzi infection. This trypanocidal activity could be due to inhibition of the peptidyl prolyl cis-trans isomerase activity on the T. cruzi recombinant cyclophilins tested. Furthermore, CsA and F-7-62 derivative inhibited the efflux of rhodamine 123 from T. cruzi epimastigotes, suggesting an interference with a P-glycoprotein activity. Moreover, H-7-94 and F-7-62 CsA analogues were not toxic as shown by cell viability and by aminopyrine-N-demethylase activity on mammalian cells. Our results show that H-7-94, F-7-62 and MeVal-4 CsA analogues expressed the highest inhibiting effects on T. cruzi, being promissory parasiticidal drugs worthy of further studies.

Copyright

Corresponding author

*Corresponding author: Av. Paseo Colón 568 (1063)Buenos Aires, Argentina. Tel: +5411 4331 4010. Fax: +5411 4331 7142. E-mail: jacbua@yahoo.com

References

Hide All
Bertault-Peres, P., Bonfils, C., Fabre, G., Just, S., Cano, J. P. and Maurel, P. (1987). Metabolism of cyclosporin A. II. Implication of the macrolide antibiotic-inducible cytochrome P-450 3c from rabbit liver microsomes. Drug Metabolism and Disposition: the Biological Fate of Chemicals 15, 391398.
Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 72, 248254.
Bell, A., Roberts, H. C. and Chappell, L. H. (1996). The anti-parasite effects of cyclosporin A: Possible drug targets and clinical applications. General Pharmacology 27, 963971.
Billich, A., Hammerschmid, F., Peichl, P., Wenger, R., Zenke, G., Quesniaux, V. and Rosenwirth, B. (1995). Mode of action of SDZ NIM 811, a nonimmunosuppressive cyclosporin A analog with activity against human immunodeficiency virus (HIV) type 1: interference with HIV protein-cyclophilin A interactions. Journal of Virology 69, 24512461.
Búa, J., Åslund, L., Pereyra, N., García, G. A., Bontempi, E. J. and Ruiz, A. M. (2001). Characterisation of a cyclophilin isoform in Trypanosoma cruzi. FEMS Microbiology Letters 200, 4347.
Búa, J., Ruiz, A. M., Potenza, M. and Fichera, L. E. (2004). In vitro anti-parasitic activity of Cyclosporin A analogs on Trypanosoma cruzi. Bioorganic and Medicinal Chemistry Letters 14, 46334637.
Carraro, R., Búa, J., Ruiz, A. M. and Paulino, M. (2007). Modelling and study of Cyclosporin A and related compounds in complexes with a Trypanosoma cruzi cyclophilin. Journal of Molecular Graphics and Modelling Sept. 26, E Pub ahead of print. doi: 10.1016/j.jmgm.2006.09.008.
Carrero, J. C., Lugo, H., Perez, D. G., Ortiz-Martínez, C. and Laclette, J. P. (2004). Cyclosporin A inhibits calcineurin (phosphatase 2B) and P-glycoprotein activity in Entamoeba histolytica. International Journal for Parasitology 34, 10911097. doi: 10.1016/j.ijpara.2004.05.004.
Dallagiovanna, B., Gamarro, F. and Castanys, S. (1996). Molecular characterization of a P-glycoprotein-related tcpgp2 gene in Trypanosoma cruzi. Molecular and Biochemical Parasitology 75, 145157. doi: 10.1006/expr.1994.1061.
Efferth, T., Lohrke, H. and Volm, M. (1989). Reciprocal correlation between expression of P-glycoprotein and accumulation of rhodamine 123 in human tumors. Anticancer Research 9, 16331637.
Fischer, G., Bang, H. and Mech, C. (1984). Determination of enzymatic catalysis for the cis-trans isomerization of peptide binding in proline-containing peptides. Biomedica Biochimica Acta 43, 11011111.
Fotakis, G. and Timbrell, J. A. (2006). In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicology Letters 160, 171177. doi: 10.1016/j.toxlet.2005.07.001.
Galat, A. (1999). Variations of sequences and amino acid compositions of proteins that sustain their biological functions: An analysis of the cyclophilin family of proteins. Archives of Biochemistry and Biophysics 371, 149162. doi: 10.1006/abbi.1999.1434.
Gan, L. S., Moseley, M. A., Khosla, B., Augustijns, P. F., Bradshaw, T. P., Hendren, R. W. and Thakker, D. R. (1996). CYP3A-like cytochrome P450-mediated metabolism and polarized efflux of cyclosporine A in Caco-2. Drug Metabolism and Disposition: the Biological Fate of Chemicals 24, 344349.
Grau, G. E., Gretener, D. and Lambert, P. H. (1987). Prevention of murine cerebral malaria by low-dose cyclosporin A. Immunology 61, 521525.
Guillouzo, A. (1998). Liver cell models in vitro toxicology. Environmental Health Perspectives 106, 511532.
Jover, R., Ponsoda, X., Gómez-Lechon, M. J. and Castell, J. V. (1992). Potentiation of heroin and methadone hepatotoxicity by ethanol: an in vitro study using cultured human hepatocytes. Xenobiotica 22, 471478.
Handschumacher, R. E., Harding, M. W., Rice, J., Drugge, R. J. and Speicher, D. W. (1984). Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science 226, 544547.
Hansson, M. J., Mattiasson, G., Mansson, R., Karlsson, J., Keep, M. F., Waldmeier, P., Ruegg, U. T., Dumont, J. M., Besseghir, K. and Elmer, E. (2004). The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. Journal of Bioenergetics and Biomembranes 36, 407413. doi: 10.1023/B:JOBB.0000041776.31885.45
Ko, S. Y. and Wenger, R. M. (1997). Solid-phase total synthesis of cyclosporine analogues. Helvetica Chimica Acta 80, 695705. doi: 10.1002/hlca.19970800307
Kocken, C. H. M., Van der Wel, A., Rosenwirth, B. and Thomas, A. W. (1996). Plasmodium vivax: in vitro antiparasitic effect of cyclosporins. Experimental Parasitology 84, 439443.
Kofron, J. L., Kuzmic, P., Kishore, V., Colon-Bonilla, E. and Rich, D. H. (1991). Determination of kinetic constants for peptidyl prolyl cis-trans isomerases by an improved spectrophotometric assay. Biochemistry 30, 61276134.
Liu, J., Farmer, J. D. Jr., Lane, W. S., Friedman, J., Weissman, I. and Schreiber, S. L. (1991). Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66, 807815.
Ma, S., Boerner, J. E., TiongYip, C., Weidmann, B., Ryder, N. S., Cooreman, M. P. and Lin, K. (2006). NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrobial Agents and Chemotherapy 50, 29762982. doi: 10.1128/AAC.00310-06
McCabe, R. E., Remington, J. S. and Araujo, F. G. (1985). In vivo and in vitro effects of cyclosporin A on Trypanosoma cruzi. The American Journal of Tropical Medicine and Hygiene 34, 861865.
Moncayo, A. and Ortiz Yanine, M. I. (2006) An update on Chagas disease (human American trypanosomiasis). Annals of Tropical Medicine and Parasitology 100, 663677. doi: 10.1179/136485906X112248.
Nash, T. (1953). The colorimetric estimation of formaldehyde by means of the Hantzche reaction. The Biochemical Journal 55, 416421.
Orrenius, S. (1968). Some aspects on the hydroxylation of drugs, steroid hormones and fatty acids (omega-oxidation) in rat liver microsomes. Hoppe-Seyler's Zeitschrift für physiologische Chemie 349, 16191621.
Paulino, M., Iribarne, F., Dubin, M., Aguilera-Morales, S., Tapia, O. and Stoppani, A. O. (2005). The chemotherapy of Chagas' disease: an overview. Mini Reviews in Medicinal Chemistry 5, 499519. doi: 10.1016/j.jelekin.2004.09.004
Pichard, L., Fabre, J. M., Domergue, J., Fabre, G., Saint Aubert, H., Mourad, G. and Maurel, P. (1991). Molecular mechanism of Cyclosporine A drug interactions: inducers and inhibitors of cytochrome P450 screening in primary cultures of human hepatocytes. Transplantation Proceedings 23, 978979.
Picken, N. C., Eschenlauer, S., Taylor, P., Page, A. P. and Walkinshaw, M. D. (2002). Structural and biological characterisation of the gut-associated cyclophilin B isoforms from Caenorhabditis elegans. Journal of Molecular Biology 322, 1525.
Potenza, M., Galat, A., Minning, T. A., Ruiz, A. M., Durán, R., Tarleton, R. L., Marín, M., Fichera, L. E. and Búa, J. (2006). Analysis of the Trypanosoma cruzi cyclophilin gene family and identification of Cyclosporin A binding proteins. Parasitology 132, 867882. doi: 10.1017/S0031182005009558.
Rottenberg, M. E., Cardoni, R. L., Sinagra, A., Riarte, A., Rodríguez Nantes, I., Lauricella, M. and Segura, E. L. (1991). Trypanosoma cruzi: T-Cell-dependent mechanism of resistance during chronic infection. Experimental Parasitology 73, 127136.
Ruiz, A. M., Esteva, M., Cabeza Meckert, P., Laguens, R. P. and Segura, E. L. (1985). Protective immunity and pathology induced by inoculation of mice with different subcellular fractions of Trypanosoma cruzi. Acta Tropica 42, 299309.
Silverman, J. A., Hayes, M. L., Luft, B. J. and Joiner, K. A. (1997). Characterization of anti-Toxoplasma activity of SDZ 215–918, a cyclosporin derivative lacking immunosuppressive and peptidyl-prolyl-isomerase-inhibiting activity: possible role of a P glycoprotein in Toxoplasma physiology. Antimicrobial Agents and Chemotherapy 41, 18591866.
Song, C. H., Lee, J. S., Kim, H. J., Park, J. K., Paik, T. H. and Jo, E. K. (2003). Interleukin-8 is differentially expressed by human-derived monocytic cell line U937 infected with Mycobacterium tuberculosis H37Rv and Mycobacterium marinum. Infection and Immunity 71, 54805487.
Takahashi, N., Hayano, T. and Suzuki, M. (1989). Peptidyl-prolyl cis-trans isomerase is the Cyclosporin A-binding protein cyclophilin. Nature, London 337, 473475. doi: 10.1038/337473a0.
Traber, R., Kobel, H., Loosli, H. R., Senn, H., Rosenwirth, B. and Lawen, A. (1994). [MeIle4] cyclosporin, a novel natural cyclosporin with anti-HIV activity: structural elucidation, biosynthesis and biological properties. Antiviral Chemistry and Chemotherapy 5, 331339.
Torres, C., Barreiro, L., Dallagiovanna, B., Gamarro, F. and Castanys, S. (1999). Characterization of a new ATP-binding cassette transporter in Trypanosoma cruzi associated to a L1Tc retrotransposon. Biochimica et Biophysica Acta 1489, 428432.
Urbina, J. A. and Docampo, R. (2003). Specific chemotherapy of Chagas disease: controversies and advances. Trends in Parasitology 19, 495501.
Waldmeier, P. C., Feldtrauer, J. J., Qian, T. and Lemasters, J. J. (2002). Inhibition of the mitochondrial permeability transition by the non-immunosuppressive cyclosporin derivative NIM811. Molecular Pharmacology 62, 2229.
Watkins, P. B. (1990). The role of cytochrome P450 in Cyclosporin metabolism. Journal of the American Academy of Dermatology 23, 13011309.
Wenger, R. M. (1986). Synthesis of Cyclosporin and analogues: structural and conformational requirements for immunosuppresive activity. Progress in Allergy 38, 4664.
Yoshimura, R., Yoshimura, N., Ohyama, A., Ohmachi, T., Yamamoto, K., Kishimoto, T. and Wada, S. (1999). The effect of immunosuppressive agents (FK-506, rapamycin) on renal P450 systems in rat models. The Journal of Pharmacy and Pharmacology 51, 941948.
Zahner, H. and Schultheiss, K. (1987). Effect of cyclosporin A and some derivatives in Litomosoides carinii-infected Mastomys natalensis. Journal of Helminthology 61, 282290.
Zenke, G., Baumann, G., Wenger, R., Hiestand, P., Quesniaux, V., Andersen, E. and Schreier, M. H. (1993). Molecular mechanisms of immunosuppression by cyclosporins. Annals of the New York Academy of Sciences 685, 330335.

Keywords

Anti-Trypanosoma cruzi effects of cyclosporin A derivatives: possible role of a P-glycoprotein and parasite cyclophilins

  • J. BÚA (a1), L. E. FICHERA (a1), A. G. FUCHS (a2) (a3), M. POTENZA (a1), M. DUBIN (a2), R. O. WENGER (a4), G. MORETTI (a1), C. M. SCABONE (a1) and A. M. RUIZ (a1)...

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed