Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death

Detalhes bibliográficos
Autor(a) principal: Kessler, Rafael Luis
Data de Publicação: 2013
Outros Autores: Soares, Maurilio José, Probst, Christian Macagnan, Krieger, Marco Aurélio
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/16039
Resumo: Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.
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spelling Kessler, Rafael LuisSoares, Maurilio JoséProbst, Christian MacagnanKrieger, Marco Aurélio2016-10-03T13:16:47Z2016-10-03T13:16:47Z2013KESSLER, Rafael Luis et al. Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death. PLoS ONE, v. 8, n. 1, p. 1-16, 2013.1932-6203https://www.arca.fiocruz.br/handle/icict/16039engIratxe PueblaTrypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell deathinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.The protozoan parasite Trypanosoma cruzi displays similarities to fungi in terms of its sterol lipid biosynthesis, as ergosterol and other 24-alkylated sterols are its principal endogenous sterols. The sterol pathway is thus a potential drug target for the treatment of Chagas disease. We describe here a comparative study of the growth inhibition, ultrastructural and physiological changes leading to the death of T. cruzi cells following treatment with the sterol biosynthesis inhibitors (SBIs) ketoconazole and lovastatin. We first calculated the drug concentration inhibiting epimastigote growth by 50% (EC50/72 h) or killing all cells within 24 hours (EC100/24 h). Incubation with inhibitors at the EC50/72 h resulted in interesting morphological changes: intense proliferation of the inner mitochondrial membrane, which was corroborated by flow cytometry and confocal microscopy of the parasites stained with rhodamine 123, and strong swelling of the reservosomes, which was confirmed by acridine orange staining. These changes to the mitochondria and reservosomes may reflect the involvement of these organelles in ergosterol biosynthesis or the progressive autophagic process culminating in cell lysis after 6 to 7 days of treatment with SBIs at the EC50/72 h. By contrast, treatment with SBIs at the EC100/24 h resulted in rapid cell death with a necrotic phenotype: time-dependent cytosolic calcium overload, mitochondrial depolarization and reservosome membrane permeabilization (RMP), culminating in cell lysis after a few hours of drug exposure. We provide the first demonstration that RMP constitutes the “point of no return” in the cell death cascade, and propose a model for the necrotic cell death of T. cruzi. Thus, SBIs trigger cell death by different mechanisms, depending on the dose used, in T. cruzi. These findings shed new light on ergosterol biosynthesis and the mechanisms of programmed cell death in this ancient protozoan parasite.Trypanosoma cruziSterol Biosynthesis InhibitorsEsteróisCetoconazolInibidores de 14-alfa DesmetilaseLovastatinaInibidores de Hidroximetilglutaril-CoA Redutasesinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-83074https://www.arca.fiocruz.br/bitstream/icict/16039/1/license.txt0271fb68963c017aa933c7aff60379f4MD51ORIGINALTrypanosoma cruzi Response to Sterol Biosynthesis Inhibitors.PDFTrypanosoma cruzi Response to Sterol Biosynthesis Inhibitors.PDFapplication/pdf5416806https://www.arca.fiocruz.br/bitstream/icict/16039/2/Trypanosoma%20cruzi%20Response%20to%20Sterol%20Biosynthesis%20Inhibitors.PDF129fb4ef9e35aed5b882214a68eb086bMD52TEXTTrypanosoma cruzi Response to Sterol Biosynthesis Inhibitors.PDF.txtTrypanosoma 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dc.title.pt_BR.fl_str_mv Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death
title Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death
spellingShingle Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death
Kessler, Rafael Luis
Trypanosoma cruzi
Sterol Biosynthesis Inhibitors
Esteróis
Cetoconazol
Inibidores de 14-alfa Desmetilase
Lovastatina
Inibidores de Hidroximetilglutaril-CoA Redutases
title_short Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death
title_full Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death
title_fullStr Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death
title_full_unstemmed Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death
title_sort Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death
author Kessler, Rafael Luis
author_facet Kessler, Rafael Luis
Soares, Maurilio José
Probst, Christian Macagnan
Krieger, Marco Aurélio
author_role author
author2 Soares, Maurilio José
Probst, Christian Macagnan
Krieger, Marco Aurélio
author2_role author
author
author
dc.contributor.author.fl_str_mv Kessler, Rafael Luis
Soares, Maurilio José
Probst, Christian Macagnan
Krieger, Marco Aurélio
dc.subject.en.pt_BR.fl_str_mv Trypanosoma cruzi
Sterol Biosynthesis Inhibitors
topic Trypanosoma cruzi
Sterol Biosynthesis Inhibitors
Esteróis
Cetoconazol
Inibidores de 14-alfa Desmetilase
Lovastatina
Inibidores de Hidroximetilglutaril-CoA Redutases
dc.subject.decs.pt_BR.fl_str_mv Esteróis
Cetoconazol
Inibidores de 14-alfa Desmetilase
Lovastatina
Inibidores de Hidroximetilglutaril-CoA Redutases
description Fundação Oswaldo Cruz. Instituto Carlos Chagas. Curitiba, PR, Brasil.
publishDate 2013
dc.date.issued.fl_str_mv 2013
dc.date.accessioned.fl_str_mv 2016-10-03T13:16:47Z
dc.date.available.fl_str_mv 2016-10-03T13:16:47Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv KESSLER, Rafael Luis et al. Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death. PLoS ONE, v. 8, n. 1, p. 1-16, 2013.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/16039
dc.identifier.issn.pt_BR.fl_str_mv 1932-6203
identifier_str_mv KESSLER, Rafael Luis et al. Trypanosoma cruzi response to Sterol Biosynthesis Inhibitors: morphophysiological alterations leading to cell death. PLoS ONE, v. 8, n. 1, p. 1-16, 2013.
1932-6203
url https://www.arca.fiocruz.br/handle/icict/16039
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Iratxe Puebla
publisher.none.fl_str_mv Iratxe Puebla
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
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https://www.arca.fiocruz.br/bitstream/icict/16039/3/Trypanosoma%20cruzi%20Response%20to%20Sterol%20Biosynthesis%20Inhibitors.PDF.txt
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