Hostname: page-component-78c5997874-s2hrs Total loading time: 0 Render date: 2024-11-03T05:12:38.901Z Has data issue: false hasContentIssue false
  • English
  • Français

Inhibition of NAD+-dependent histone deacetylases (sirtuins) causes growth arrest and activates both apoptosis and autophagy in the pathogenic protozoan Trypanosoma cruzi

Published online by Cambridge University Press:  06 February 2014

PHERCYLES VEIGA-SANTOS ,
LISSA CATHERINE REIGNAULT ,
KILIAN HUBER ,
FRANZ BRACHER ,
WANDERLEY DE SOUZA  and
TECIA MARIA ULISSES DE CARVALHO
PHERCYLES VEIGA-SANTOS
Affiliation:
Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil
LISSA CATHERINE REIGNAULT
Affiliation:
Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil
KILIAN HUBER
Affiliation:
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, A-1090 Vienna, Austria
FRANZ BRACHER
Affiliation:
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany
WANDERLEY DE SOUZA
Affiliation:
Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil Instituto Nacional de Metrologia, Qualidade e Tecnologia – Inmetro, Duque de Caxias, Rio de Janeiro, Brazil
TECIA MARIA ULISSES DE CARVALHO*
Affiliation:
Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil
*
*Corresponding author: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Bloco G, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, CEP 21949-900, Brazil. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

Chagas disease, which is caused by the parasite Trypanosoma cruzi, affects approximately 7–8 million people in Latin America. The drugs available to treat this disease are ineffective against chronic phase disease and are associated with toxic side effects. Therefore, the development of new compounds that can kill T. cruzi at low concentrations is critically important. Herein, we report the effects of a novel 3-arylideneindolin-2-one that inhibits sirtuins, which are highly conserved proteins that are involved in a variety of physiological processes. The compound KH-TFMDI was tested against the epimastigote, trypomastigote and amastigote forms of T. cruzi, and its effects were evaluated using flow cytometry, light and electron microscopy. KH-TFMDI inhibited the replication of T. cruzi intracellular amastigotes with an IC50 of 0·5±0·2 μm, which is significantly lower than the IC50 of benznidazole. The compound also lysed the highly infectious bloodstream trypomastigotes (BST) with LC50 values of 0·8±0·3 μm at 4 °C and 2·5±1·1 μm at 37 °C. KH-TFMDI inhibited cytokinesis and induced several morphological changes in the parasite, leading to its death by apoptosis and autophagy. This study highlights sirtuins as a potential new target for Chagas disease therapy.

Keywords

Chagas diseasesirtuin inhibitorsKH-TFMDIautophagyapoptosis
Type
Research Article
Information
Parasitology , Volume 141 , Issue 6 , May 2014 , pp. 814 - 825
Copyright
Copyright © Cambridge University Press 2014 

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

Alsford, S., Kawahara, T., Isamah, C. and Horn, D. (2007). A sirtuin in the African trypanosome is involved in both DNA repair and telomeric gene silencing but is not required for antigenic variation. Molecular Microbiology 63, 724–736. doi: 10.1111/j.1365-2958.2006.05553.x.Google Scholar
Baur, J. A., Ungvari, Z., Minor, R. K., Le Couteur, D. G. and Cabo, R. (2012). Are sirtuins viable targets for improving healthspan and lifespan? Nature Review Drug Discovery 11, 443–461. doi: 10.1038/nrd3738.CrossRefGoogle ScholarPubMed
Bisaggio, D. F. R., Adade, C. M. and Souto- Padrón, T. (2008). In vitro effects of suramin on Trypanosoma cruzi . International Journal of Antimicrobial Agents 31, 282–286. doi: 10.1016/j.ijantimicag.2007.11.001.Google Scholar
Camargo, E. P. (1964). Growth and differentiation in Trypanosoma cruzi. Origin of metacyclic trypanosomes in liquid media. Revista do Instituto de Medicina tropical de São Paulo 6, 93–100.Google Scholar
Cogo, J., Caleare, A. O., Ueda-Nakamura, T., Dias Filho, B. P., Ferreira, I. C. P. and Nakamura, C. V. (2012). Trypanocidal activity of guaianolide obtained from Tanacetum parthenium (L.) Schultz-Bip. and its combinational effect with benznidazole. Phytomedicine 1, 59–66. doi: 10.1016/j.phymed.2012.09.011.Google Scholar
Dantas, A. P., Barbosa, H. S. and De Castro, S. L. (2003). Biological and ultrastructural effects of the anti-microtubule agent taxol against Trypanosoma cruzi . Journal of Submicroscopic Cytology and Pathology 35, 287–294.Google Scholar
Fernandes, M. C., Da Silva, E. N. Jr., Pinto, A. V., De Castro, S. L. and Menna-Barreto, R. F. S. (2012). A novel triazolic naphthofuranquinone induces autophagy in reservosomes and impairment of mitosis in Trypanosoma cruzi . Parasitology 139, 26–36. doi: 10.1017/S0031182011001612.Google Scholar
Gump, J. M. and Thorburn, A. (2011). Autophagy and apoptosis: what is the connection? Trends in Cell Biology 21, 387–392. doi: 10.1016/j.tcb.2011.03.007.CrossRefGoogle ScholarPubMed
Henriques, C., Moreira, T. L. B., Maia-Brigagão, C., Henriques-Pons, A., Carvalho, T. M. U. and De Souza, W. (2011). Tetrazolium salts based methods for high-throughput evaluation of anti-parasite chemotherapy. Analytical Methods 3, 2148–2155.CrossRefGoogle Scholar
Huber, K., Schemies, J., Uciechowska, U., Wagner, J. M., Rumpf, T., Lewrick, F., Süss, R., Sippl, W., Jung, M. and Bracher, F. (2010). Novel 3-arylideneindolin-2-ones as inhibitors of NAD+-dependent histone deacetylases (sirtuins). Journal of Medicinal Chemistry 53, 1383–1386. doi: 10.1021/jm901055u.Google Scholar
Kohl, L. and Bastin, P. (2003). The flagellum of trypanosomes. International Review of Cytology 244, 227–285.Google Scholar
Kohl, L., Robinson, D. and Bastin, P. (2003). Novel roles for the flagellum in cell morphogenesis and cytokinesis of trypanosomes. EMBO Journal 22, 5336–5346.Google Scholar
Lee, S. H., Meng, X. W., Flatten, K. S., Loegering, D. A. and Kaufmann, S. H. (2013). Phosphatidylserine exposure during apoptosis reflects bidirectional trafficking between plasma membrane and cytoplasm. Cell Death and Differentiation 20, 64–76. doi: 10.1038/cdd.2012.93.Google Scholar
Macedo-Silva, S. T., Silva, T. L. A. O., Urbina, J. A., De Souza, W. and Rodrigues, J. C. F. (2011). Antiproliferative, ultrastructural, and physiological effects of amiodarone on promastigote and amastigote forms of Leishmania amazonensis . Molecular Biology International 876021. doi: 10.4061/2011/876021.Google ScholarPubMed
Meirelles, M. N., De Araújo Jorge, T. C. and De Souza, W. (1982). Interaction of Trypanosoma cruzi with macrophages in vitro: dissociation of the attachment and internalization phases by low temperature and cytochalasin B. Zeitschrift für Parasitenkunde 68, 7–14.Google Scholar
Nakagawa, T. and Guarente, L. (2011). Sirtuins at a glance. Journal of Cell Science 124, 833–838. doi: 10.1242/jcs.081067.Google Scholar
Religa, A. A. and Waters, A. P. (2012). Sirtuins of parasitic protozoa: in search of function(s). Molecular and Biochemical Parasitology 185, 71–88. doi: 10.1016/j.molbiopara.2012.08.003.Google Scholar
Salminen, A. and Kaarniranta, K. (2009). SIRT1: regulation of longevity via autophagy. Cellular Signalling 21, 1356–1360. doi: 10.1016/j.cellsig.2009.02.014.Google Scholar
Soeiro, M. N. C. and Castro, S. L. (2011). Screening of potential anti-Trypanosoma cruzi candidates: in vitro and in vivo studies. Open Medicinal Chemistry Journal 5, 21–30. doi: 10.2174/1874104501105010021.Google Scholar
Silva, C. F., Daliry, A., Bernardino, P., Silva, P. B., Akay, S., Banerjee, B., Farahat, A. A., Fisher, M., Hu, L., Kumar, A., Liu, Z., Stephens, C. E., Boykin, D. and Soeiro, M. N. C. (2011). The efficacy of novel arylimidamides against Trypanosoma cruzi in vitro . Parasitology 138, 1863–1869.Google Scholar
Tavares, J., Ouaissi, A., Kong Thoo Lin, P., Loureireo, I., Kaur, S., Roy, N. and Cordeiro-Da-Silva, A. (2010). Bisnaphthalimidopropyl derivatives as inhibitors of Leishmania SIR2 related protein 1. ChemMedChem 5, 140–147.Google Scholar
Urbina, J. A. (2010). New insights in Chagas’ disease treatment. Drugs of the Future 35, 409–419. doi: 10.1358/dof.2010.35.5.1484391.Google Scholar
Veiga-Santos, P., Barrias, E. S., Santos, J. F. C., Moreira, T. L. B., Carvalho, T. M. U. and De Souza, W. (2012). Effects of amiodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi . International Journal of Antimicrobial Agents 40, 61–71. doi: 10.1016/j.ijantimicag.2012.03.009.Google Scholar
Verdin, E., Hirschey, M. D., Finley, L. W. S. and Haigis, M. C. (2010). Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends in Biochemical Sciences 35, 669–675. doi: 10.1016/j.tibs.2010.07.003.Google Scholar
Vergnes, B., Sereno, D., Madjidian-Sereno, N., Lemesre, J. L. and Ouaissi, A. (2002). Cytoplasmic SIR2 homologue overexpression promotes survival of Leishmania parasites by preventing programmed cell death. Gene 296, 139–150. doi: 10.1016/S0378-1119(02)00842-9.Google Scholar
Vergnes, B., Vanhille, L., Ouaissi, A. and Sereno, D. (2005). Stage-specific antileishmanial activity of an inhibitor of SIR2 histone deacetylase. Acta Tropica 94, 107–115. doi: 10.1016/j.actatropica.2005.03.004.Google Scholar
Voogd, T. E., Vansterkenburg, E. L. M., Wilting, J. and Janssen, L. H. M. (1993). Recent research on the biological activity of suramin. Pharmacological Reviews 46, 177–199.Google Scholar
Zemzoumi, K., Sereno, D., Francois, C., Guilvard, E., Lemesre, J. L. and Ouaissi, A. (1998). Leishmania major: cell type dependent distribution of a 43 kDa antigen related to silent information regulatory-2 protein family. Biology of the Cell 90, 239–245.Google Scholar
Zheng, W. (2013). Sirtuins as emerging anti-parasitic targets. European Journal of Medicinal Chemistry 59, 132–140. doi: 10.1016/j.ejmech.2012.11.014.Google Scholar
Zingales, B., Andrade, S. G., Briones, M. R. S., Campbell, D. A., Chiari, E., Fernandes, O., Guhl, F., Lages-Silva, E., Macedo, A. M., Machado, C. R., Miles, M. A., Romanha, A. J., Sturm, N. R., Tibayrenc, M. and Schijman, A. G. (2009). A new consensus for Trypanosoma cruzi intraspecific nomenclature: second revision meeting recommends TcI to TcVI. Memórias do Instituto Oswaldo Cruz 104, 1051–1054.Google Scholar
World Health Organization ( 2013 ). Control of Chagas Disease. Fact sheet No 340 Updated March 2013. World Health Organization, Geneva, Switzerland.Google Scholar
Supplementary material: Image

Veiga-Santos Supplementary Material

Figure S1

Download Veiga-Santos Supplementary Material(Image)
Image 35.2 MB
Supplementary material: Image

Veiga-Santos Supplementary Material

Figure S2

Download Veiga-Santos Supplementary Material(Image)
Image 26.1 MB