Hostname: page-component-78c5997874-s2hrs Total loading time: 0 Render date: 2024-11-10T12:40:54.815Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  09 October 2007

J. BÚA ,
L. E. FICHERA ,
A. G. FUCHS ,
M. POTENZA ,
M. DUBIN ,
R. O. WENGER ,
G. MORETTI ,
C. M. SCABONE  and
A. M. RUIZ
J. BÚA*
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
L. E. FICHERA
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
A. G. FUCHS
Affiliation:
Centro de Estudios Farmacológicos y Botánicos, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina Centro de altos estudios de Ciencias de la Salud, Universidad Abierta Interamericana, Buenos Aires, Argentina
M. POTENZA
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
M. DUBIN
Affiliation:
Centro de Estudios Farmacológicos y Botánicos, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
R. O. WENGER
Affiliation:
Wenger Chemtech, CH-4125Riehen, Switzerland
G. MORETTI
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
C. M. SCABONE
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
A. M. RUIZ
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
*
*Corresponding author: Av. Paseo Colón 568 (1063)Buenos Aires, Argentina. Tel: +5411 4331 4010. Fax: +5411 4331 7142. E-mail: jacbua@yahoo.com
Get access Rights & Permissions [Opens in a new window]

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.

Keywords

Trypanosoma cruzicyclosporin A derivativescyclophilinsP-glycoproteinparasiticidal activity
Type
Research Article
Information
Parasitology , Volume 135 , Issue 2 , February 2008 , pp. 217 - 228
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

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, 391–398.Google ScholarPubMed
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, 248–254.Google Scholar
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, 963–971.Google Scholar
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, 2451–2461.Google Scholar
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, 43–47.Google Scholar
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, 4633–4637.Google Scholar
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.Google Scholar
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, 1091–1097. doi: 10.1016/j.ijpara.2004.05.004.Google Scholar
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, 145–157. doi: 10.1006/expr.1994.1061.Google Scholar
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, 1633–1637.Google Scholar
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, 1101–1111.Google Scholar
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, 171–177. doi: 10.1016/j.toxlet.2005.07.001.Google Scholar
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, 149–162. doi: 10.1006/abbi.1999.1434.Google Scholar
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, 344–349.Google Scholar
Grau, G. E., Gretener, D. and Lambert, P. H. (1987). Prevention of murine cerebral malaria by low-dose cyclosporin A. Immunology 61, 521–525.Google Scholar
Guillouzo, A. (1998). Liver cell models in vitro toxicology. Environmental Health Perspectives 106, 511–532.Google Scholar
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, 471–478.CrossRefGoogle Scholar
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, 544–547.CrossRefGoogle ScholarPubMed
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, 407–413. doi: 10.1023/B:JOBB.0000041776.31885.45Google Scholar
Ko, S. Y. and Wenger, R. M. (1997). Solid-phase total synthesis of cyclosporine analogues. Helvetica Chimica Acta 80, 695–705. doi: 10.1002/hlca.19970800307Google Scholar
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, 439–443.Google Scholar
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, 6127–6134.Google Scholar
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, 807–815.Google Scholar
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, 2976–2982. doi: 10.1128/AAC.00310-06Google Scholar
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, 861–865.Google Scholar
Moncayo, A. and Ortiz Yanine, M. I. (2006) An update on Chagas disease (human American trypanosomiasis). Annals of Tropical Medicine and Parasitology 100, 663–677. doi: 10.1179/136485906X112248.Google Scholar
Nash, T. (1953). The colorimetric estimation of formaldehyde by means of the Hantzche reaction. The Biochemical Journal 55, 416–421.CrossRefGoogle ScholarPubMed
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, 1619–1621.Google Scholar
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, 499–519. doi: 10.1016/j.jelekin.2004.09.004Google Scholar
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, 978–979.Google Scholar
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, 15–25.Google Scholar
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, 867–882. doi: 10.1017/S0031182005009558.Google Scholar
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, 127–136.Google Scholar
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, 299–309.Google ScholarPubMed
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, 1859–1866.Google Scholar
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, 5480–5487.Google Scholar
Takahashi, N., Hayano, T. and Suzuki, M. (1989). Peptidyl-prolyl cis-trans isomerase is the Cyclosporin A-binding protein cyclophilin. Nature, London 337, 473–475. doi: 10.1038/337473a0.Google Scholar
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, 331–339.CrossRefGoogle Scholar
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, 428–432.Google Scholar
Urbina, J. A. and Docampo, R. (2003). Specific chemotherapy of Chagas disease: controversies and advances. Trends in Parasitology 19, 495–501.Google Scholar
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, 22–29.Google Scholar
Watkins, P. B. (1990). The role of cytochrome P450 in Cyclosporin metabolism. Journal of the American Academy of Dermatology 23, 1301–1309.Google Scholar
Wenger, R. M. (1986). Synthesis of Cyclosporin and analogues: structural and conformational requirements for immunosuppresive activity. Progress in Allergy 38, 46–64.Google Scholar
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, 941–948.Google Scholar
Zahner, H. and Schultheiss, K. (1987). Effect of cyclosporin A and some derivatives in Litomosoides carinii-infected Mastomys natalensis. Journal of Helminthology 61, 282–290.Google Scholar
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, 330–335.Google Scholar