Hostname: page-component-848d4c4894-ttngx Total loading time: 0 Render date: 2024-05-17T08:35:31.030Z Has data issue: false hasContentIssue false
  • English
  • Français

Naphthoimidazoles promote different death phenotypes in Trypanosoma cruzi

Published online by Cambridge University Press:  13 March 2009

R. F. S. MENNA-BARRETO ,
J. R. CORRÊA ,
C. M. CASCABULHO ,
M. C. FERNANDES ,
A. V. PINTO ,
M. J. SOARES  and
S. L. DE CASTRO
R. F. S. MENNA-BARRETO
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, 21045-900, Brazil
J. R. CORRÊA
Affiliation:
Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, 21045-900, Brazil
C. M. CASCABULHO
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, 21045-900, Brazil
M. C. FERNANDES
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, 21045-900, Brazil
A. V. PINTO
Affiliation:
Núcleo de Pesquisas em Produtos Naturais, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21944-970, Brazil
M. J. SOARES
Affiliation:
Instituto Carlos Chagas, Fundação Oswaldo Cruz, Curitiba, PR, 81350-010, Brazil
S. L. DE CASTRO*
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, 21045-900, Brazil
*
*Corresponding author: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, FIOCRUZ, Av. Brasil 4365, 21045-900,900 Rio de Janeiro, RJ, Brazil. Tel: +55 21 2598 4534. Fax: +55 21 2598 4577. E-mail: solange@ioc.fiocruz.br
Get access Rights & Permissions [Opens in a new window]

Summary

In a screening of 65 derivatives of natural quinones using bloodstream trypomastigotes of Trypanosoma cruzi, the 3 naphthoimidazoles derived from β-lapachone – N1, N2 and N3 – were selected as the most active. Investigation of their mode of action led to the characterization of mitochondrion, reservosomes and DNA as their main targets, and stimulated further studies on death pathways. Ultrastructural analysis revealed both autophagic (autophagosomes) and apoptotic-like (membrane blebbing) phenotypes. Flow cytometry analysis showed, in N2-treated trypomastigotes, a small increase of phosphatidylserine exposure, and a large increase in the percentage of necrosis, caused by N1 or N2. These death phenotypes were not detected in treated epimastigotes. The strong increase in labelling of monodansyl cadaverine, the inhibition of the death process by wortmannin or 3-methyladenine, the overexpression of ATG genes in treated epimastigotes, together with ultrastructural evidence point to autophagy as the predominant phenotype induced by the naphthoimidazoles. However, there are other pathways occurring concomitantly with variable intensities, justifying the need to detail the molecular features involved.

Keywords

Trypanosoma cruzinaphthoimidazolesdeath pathwaysautophagy
Type
Research Article
Information
Parasitology , Volume 136 , Issue 5 , April 2009 , pp. 499 - 510
Copyright
Copyright © 2009 Cambridge University Press

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

REFERENCES

Alvarez, V. E., Kosec, G., Sant'anna, C., Turk, V., Cazzulo, J. J. and Turk, B. (2008 a). Autophagy is involved in nutritional stress response and differentiation in Trypanosoma cruzi. Journal of Biological Chemistry 283, 3454–3464.CrossRefGoogle ScholarPubMed
Alvarez, V. E., Kosec, G., Sant'anna, C., Turk, V., Cazzulo, J. J. and Turk, B. (2008 b). Blocking autophagy to prevent parasite differentiation: a possible new strategy for fighting parasitic infections? Autophagy 4, 361–363.CrossRefGoogle ScholarPubMed
Baehrecke, E. H. (2005). Autophagy: dual roles in life and death? Nature Reviews in Molecular Cell Biology 6, 505–510.CrossRefGoogle ScholarPubMed
Besteiro, S., Williams, R. A., Morrison, L. S., Coombs, G. H. and Mottram, J. C. (2006). Endosome sorting and autophagy are essential for differentiation and virulence of Leishmania major. Journal of Biological Chemistry 281, 11384–11396.CrossRefGoogle ScholarPubMed
Bursch, W. (2001). The autophagosomal-lysosomal compartment in programmed cell death. Cell Death and Differentiation 8, 569–581.CrossRefGoogle ScholarPubMed
Chai, J., Du, C., Wu, J. W., Kyin, S., Wang, X. and Shi, Y. (2000). Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature, London 406, 855–862.CrossRefGoogle ScholarPubMed
Codogno, P. and Meijer, A. J. (2006). Atg5: more than an autophagy factor. Nature Cell Biology 8, 1045–1047.CrossRefGoogle ScholarPubMed
Coura, J. R. and De Castro, S. L. (2002). A critical review on Chagas disease chemotherapy. Memórias do Instituto Oswaldo Cruz 97, 3–24.CrossRefGoogle Scholar
Damatta, R. A., Seabra, S. H., Deolindo, P., Arnholdt, A. C., Manhães, L., Goldenberg, S. and De Souza, W. (2007). Trypanosoma cruzi exposes phosphatidylserine as an evasion mechanism. FEMS Microbiology Letters 266, 29–33.CrossRefGoogle ScholarPubMed
De Souza, E. M., Menna-Barreto, R. F. S., Araújo-Jorge, T. C., Kumar, A., Hu, Q., Boykin, D. W. and Soeiro, M. N. (2006). Antiparasitic activity of aromatic diamidines is related to apoptosis-like death in Trypanosoma cruzi. Parasitology 133, 75–79.CrossRefGoogle ScholarPubMed
Deolindo, P., Teixeira-Ferreira, A. S., Melo, E. J., Arnholdt, A. C., Souza, W., Alves, E. W. and Damatta, R. A. (2005). Programmed cell death in Trypanosoma cruzi induced by Bothrops jararaca venom. Memórias do Instituto Oswaldo Cruz 100, 33–38.CrossRefGoogle ScholarPubMed
Gordeeva, A. V., Labas, Y. A. and Zvyagilskaya, R. A. (2004). Apoptosis in unicellular organisms: mechanisms and evolution. Biochemistry (Moscow) 69, 1055–1066.CrossRefGoogle ScholarPubMed
Guimarães, C. A. and Linden, R. (2004). Programmed cell death: apoptosis and alternative deathstyles. European Journal of Biochemistry 271, 1638–1650.CrossRefGoogle Scholar
Helms, M. J., Ambit, A., Appleton, P., Tetley, L., Coombs, G. H. and Mottram, J. C. (2006). Bloodstream form Trypanosoma brucei depend upon multiple metacaspases associated with RAB11-positive endosomes. Journal of Cell Science 119, 1105–1117.CrossRefGoogle ScholarPubMed
Herman, M., Gillies, S., Michels, P. A. and Rigden, D. J. (2006). Autophagy and related processes in trypanosomatids: insights from genomic and bioinformatic analyses. Autophagy 2, 107–118.CrossRefGoogle ScholarPubMed
Jamison, J. M., Gilloteaux, J., Neal, D. R. and Summers, J. L. (1999). Characterization of early events in vitamin C and K3 induced death of human prostate tumor cells. Scanning 21, 101–108.Google Scholar
Jamison, J. M., Gilloteaux, J., Taper, H. S., Calderon, P. B. and Summers, J. L. (2002). Autoschizis: a novel cell death. Biochemical Pharmacology 63, 1773–1783.CrossRefGoogle ScholarPubMed
Jannin, J. and Villa, L. (2007). An overview of Chagas disease treatment. Memórias do Instituto Oswaldo Cruz 102, 95–97.CrossRefGoogle ScholarPubMed
Klionsky, D. J. (2007). Autophagy: from phenomenology to molecular understanding in less than a decade. Nature Reviews in Molecular Cell Biology 8, 931–937.CrossRefGoogle ScholarPubMed
Klionsky, D. J., Cregg, J. M., Dunn, W. A. Jr,, Emr, S. D., Sakai, Y., Sandoval, I. V., Sibirny, A., Subramani, S., Thumm, M., Veenhuis, M. and Ohsumi, Y. (2003). A unified nomenclature for yeast autophagy-related genes. Developmental Cell 5, 539–545.CrossRefGoogle ScholarPubMed
Kosec, G., Alvarez, V. E., Agüero, F., Sánchez, D., Dolinar, M., Turk, B., Turk, V. and Cazzulo, J. J. (2006). Metacaspases of Trypanosoma cruzi: possible candidates for programmed cell death mediators. Molecular and Biochemical Parasitology 145, 18–28.CrossRefGoogle ScholarPubMed
Levine, B. and Yuan, J. (2005). Autophagy in cell death: an innocent convict? Clinical Investigation 115, 2679–2688.CrossRefGoogle ScholarPubMed
Lockshin, R. A. and Zakeri, Z. (2002). Caspase-independent cell deaths. Current Opinion in Cell Biology 14, 727–733.CrossRefGoogle ScholarPubMed
Magalhães, K. G., Passos, L. K. and Carvalho, S. O. (2004). Detection of Lymnaea columella infection by Fasciola hepatica through Multiplex-PCR. Memórias do Instituto Oswaldo Cruz 99, 421–424.CrossRefGoogle ScholarPubMed
Menna-Barreto, R. F. S., Henriques-Pons, A., Pinto, A. V., Morgado-Diaz, J. A., Soares, M. J. and De Castro, S. L. (2005). Effect of a beta-lapachone-derived naphthoimidazole on Trypanosoma cruzi: identification of target organelles. Journal of Antimicrobial Chemotherapy 56, 1034–1041.CrossRefGoogle ScholarPubMed
Menna-Barreto, R. F. S., Corrêa, J. R., Pinto, A. V., Soares, M. J. and De Castro, S. L. (2007). Mitochondrial disruption and DNA fragmentation in Trypanosoma cruzi induced by naphthoimidazoles synthesized from beta-lapachone. Parasitology Research 101, 895–905.CrossRefGoogle ScholarPubMed
Menna-Barreto, R. F. S., Salomão, K., Dantas, A. P., Santa-Rita, R. M., Soares, M. J., Barbosa, H. S. and De Castro, S. L. (2009). Different cell death pathways induced by drugs in Trypanosoma cruzi: an ultrastructural study. Micron 40, 157–168.CrossRefGoogle ScholarPubMed
Moura, K. C. G., Emery, F. S., Neves-Pinto, C., Pinto, M. C. F. R., Dantas, A. P., Salomão, K., De Castro, S. L. and Pinto, A. V. (2001). Synthesis and trypanocidal activity of naphthoquinones isolated from Tabebuia and heterocyclic derivatives: A review from an interdisciplinary study. Journal of the Brazilian Chemical Society 12, 325–338.CrossRefGoogle Scholar
Moura, K. C. G., Salomão, K., Menna-Barreto, R. F. S., Emery, F. S., Pinto, M. C. F. R., Pinto, A. V. and De Castro, S. L. (2004). Studies on the trypanocidal activity of semi-synthetic pyran[b-4,3]naphtho[1,2-d]imidazoles from β-lapachone. European Journal of Medicinal Chemistry 39, 639–645.CrossRefGoogle ScholarPubMed
Neves-Pinto, C., Dantas, A. P., Moura, K. C. G., Emery, F. S., Polequevitch, P. F., Pinto, M. C. F. R., De Castro, S. L. and Pinto, A. V. (2000). Chemical reactivity studies with naphthoquinones from Tabebuia with anti-trypanosomal efficacy. Arzneimittelforschung 50, 1120–1128.Google Scholar
Nguewa, P. A., Fuertes, M. A., Valladares, B., Alonso, C. and Pérez, J. M. (2004). Programmed cell death in trypanosomatids: a way to maximize their biological fitness? Trends in Parasitology 20, 375–380.CrossRefGoogle ScholarPubMed
Paris, C., Loiseau, P. M., Bories, C. and Breard, J. (2004). Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes. Antimicrobial Agents and Chemotherapy 48, 852–859.CrossRefGoogle ScholarPubMed
Pinto, A. V., Menna-Barreto, R. F. S. and De Castro, S. L. (2007). Naphthoquinones isolated from Tabebuia: a review about the synthesis of heterocyclic derivatives, screening against Trypanosoma cruzi and correlation structure-trypanocidal activity. In Recent Progress in Medicinal Plants (ed. Govil, J. N.), vol. 16, Phytomedicines, pp. 112–127. Studium Press, Houston, TX, USA.Google Scholar
Pinto, A. V., Neves-Pinto, C., Pinto, M. C. F. R., Santa-Rita, R. M., Pezzella, C. A. and De Castro, S. L. (1997). Trypanocidal activity of synthetic heterocyclic derivatives of active quinones from Tabebuia sp. Arzneimittelforschung 47, 74–79.Google ScholarPubMed
Reggiori, F. and Klionsky, D. J. (2002). Autophagy in the eukaryotic cell. Eukaryotic Cell 1, 11–21.CrossRefGoogle ScholarPubMed
Ricci, M. S. and Zong, W. X. (2006). Chemotherapeutic approaches for targeting cell death pathways. Oncologist 11, 342–357.CrossRefGoogle ScholarPubMed
Rodrigues, J. C. and De Souza, W. (2008). Ultrastructural alterations in organelles of parasitic protozoa induced by different classes of metabolic inhibitors. Current Pharmacological Design 14, 925–938.CrossRefGoogle ScholarPubMed
Samuilov, V. D., Oleskin, A. V. and Lagunova, E. M. (2000). Programmed cell death. Biochemistry (Moscow) 65, 873–887.Google ScholarPubMed
Singh, G., Jayanarayan, K. G. and Dey, C. S. (2005). Novobiocin induces apoptosis-like cell death in topoisomerase II over-expressing arsenite resistant Leishmania donovani. Molecular and Biochemical Parasitology 141, 57–69.CrossRefGoogle ScholarPubMed
Tsujimoto, Y. and Shimizu, S. (2005). Another way to die: autophagic programmed cell death. Cell Death and Differentiation 12, 1528–1534.CrossRefGoogle ScholarPubMed
Van den Eijnde, S. M., Boshart, L., Baehrecke, E. H., De Zeeuw, C. I., Reutelingsperger, C. P. and Vermeij-Keers, C. (1998). Cell surface exposure of phosphatidylserine during apoptosis is phylogenetically conserved. Apoptosis 3, 9–16.CrossRefGoogle ScholarPubMed
Verma, N. K., Singh, G. and Dey, C. S. (2007). Miltefosine induces apoptosis in arsenite-resistant Leishmania donovani promastigotes through mitochondrial dysfunction. Experimental Parasitology 116, 1–13.CrossRefGoogle ScholarPubMed
Wanderley, J. L., Moreira, M. E., Benjamin, A., Bonomo, A. C. and Barcinski, M. A. (2006). Mimicry of apoptotic cells by exposing phosphatidylserine participates in the establishment of amastigotes of Leishmania (L) amazonensis in mammalian hosts. Journal of Immunology 176, 1834–1839.CrossRefGoogle ScholarPubMed
Yorimitsu, T. and Klionsky, D. J. (2007). Eating the endoplasmic reticulum: quality control by autophagy. Trends in Cell Biology 17, 279–285.CrossRefGoogle ScholarPubMed
Zong, W. X. and Thompson, C. B. (2006). Necrotic death as a cell fate. Genes and Development 20, 1–15.CrossRefGoogle ScholarPubMed