Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.

Detalhes bibliográficos
Autor(a) principal: Rocha, Clarissa Ribeiro Reily
Data de Publicação: 2014
Outros Autores: Garcia, Camila Carrião Machado, Vieira, Debora Braga, Quinet, Annabel, Lima, Leonardo Carmo de Andrade, Munford, Veridiana, Belizário, José Ernesto, Menck, Carlos Frederico Martins
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UFOP
Texto Completo: http://www.repositorio.ufop.br/handle/123456789/5611
https://doi.org/10.1038/cddis.2014.465
Resumo: Malignant glioma is a severe type of brain tumor with a poor prognosis and few options for therapy. The main chemotherapy protocol for this type of tumor is based on temozolomide (TMZ), albeit with limited success. Cisplatin is widely used to treat several types of tumor and, in association with TMZ, is also used to treat recurrent glioma. However, several mechanisms of cellular resistance to cisplatin restrict therapy efficiency. In that sense, enhanced DNA repair, high glutathione levels and functional p53 have a critical role on cisplatin resistance. In this work, we explored several mechanisms of cisplatin resistance in human glioma. We showed that cellular survival was independent of the p53 status of those cells. In addition, in a host-cell reactivation assay using cisplatin-treated plasmid, we did not detect any difference in DNA repair capacity. We demonstrated that cisplatin-treated U138MG cells suffered fewer DNA double-strand breaks and DNA platination. Interestingly, the resistant cells carried higher levels of intracellular glutathione. Thus, preincubation with the glutathione inhibitor buthionine sulfoximine (BSO) induced massive cell death, whereas N-acetyl cysteine, a precursor of glutathione synthesis, improved the resistance to cisplatin treatment. In addition, BSO sensitized glioma cells to TMZ alone or in combination with cisplatin. Furthermore, using an in vivo model the combination of BSO, cisplatin and TMZ activated the caspase 3–7 apoptotic pathway. Remarkably, the combined treatment did not lead to severe side effects, while causing a huge impact on tumor progression. In fact, we noted a remarkable threefold increase in survival rate compared with other treatment regimens. Thus, the intracellular glutathione concentration is a potential molecular marker for cisplatin resistance in glioma, and the use of glutathione inhibitors, such as BSO, in association with cisplatin and TMZ seems a promising approach for the therapy of such devastating tumors.
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spelling Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.Malignant glioma is a severe type of brain tumor with a poor prognosis and few options for therapy. The main chemotherapy protocol for this type of tumor is based on temozolomide (TMZ), albeit with limited success. Cisplatin is widely used to treat several types of tumor and, in association with TMZ, is also used to treat recurrent glioma. However, several mechanisms of cellular resistance to cisplatin restrict therapy efficiency. In that sense, enhanced DNA repair, high glutathione levels and functional p53 have a critical role on cisplatin resistance. In this work, we explored several mechanisms of cisplatin resistance in human glioma. We showed that cellular survival was independent of the p53 status of those cells. In addition, in a host-cell reactivation assay using cisplatin-treated plasmid, we did not detect any difference in DNA repair capacity. We demonstrated that cisplatin-treated U138MG cells suffered fewer DNA double-strand breaks and DNA platination. Interestingly, the resistant cells carried higher levels of intracellular glutathione. Thus, preincubation with the glutathione inhibitor buthionine sulfoximine (BSO) induced massive cell death, whereas N-acetyl cysteine, a precursor of glutathione synthesis, improved the resistance to cisplatin treatment. In addition, BSO sensitized glioma cells to TMZ alone or in combination with cisplatin. Furthermore, using an in vivo model the combination of BSO, cisplatin and TMZ activated the caspase 3–7 apoptotic pathway. Remarkably, the combined treatment did not lead to severe side effects, while causing a huge impact on tumor progression. In fact, we noted a remarkable threefold increase in survival rate compared with other treatment regimens. Thus, the intracellular glutathione concentration is a potential molecular marker for cisplatin resistance in glioma, and the use of glutathione inhibitors, such as BSO, in association with cisplatin and TMZ seems a promising approach for the therapy of such devastating tumors.2015-09-22T19:06:46Z2015-09-22T19:06:46Z2014info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfROCHA, C. R. R. et al. Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo. Cell Death & Disease, v. 5, p. e1505, 2014. Disponível em: <https://www.nature.com/articles/cddis2014465>. Acesso em: 22 maio 2015.2041-4889http://www.repositorio.ufop.br/handle/123456789/5611https://doi.org/10.1038/cddis.2014.465This work is licensed under a Creative Commons Attribution 4.0 International Licence. Fonte: o próprio artigo.info:eu-repo/semantics/openAccessRocha, Clarissa Ribeiro ReilyGarcia, Camila Carrião MachadoVieira, Debora BragaQuinet, AnnabelLima, Leonardo Carmo de AndradeMunford, VeridianaBelizário, José ErnestoMenck, Carlos Frederico Martinsengreponame:Repositório Institucional da UFOPinstname:Universidade Federal de Ouro Preto (UFOP)instacron:UFOP2019-07-31T13:11:34Zoai:repositorio.ufop.br:123456789/5611Repositório InstitucionalPUBhttp://www.repositorio.ufop.br/oai/requestrepositorio@ufop.edu.bropendoar:32332019-07-31T13:11:34Repositório Institucional da UFOP - Universidade Federal de Ouro Preto (UFOP)false
dc.title.none.fl_str_mv Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.
title Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.
spellingShingle Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.
Rocha, Clarissa Ribeiro Reily
title_short Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.
title_full Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.
title_fullStr Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.
title_full_unstemmed Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.
title_sort Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.
author Rocha, Clarissa Ribeiro Reily
author_facet Rocha, Clarissa Ribeiro Reily
Garcia, Camila Carrião Machado
Vieira, Debora Braga
Quinet, Annabel
Lima, Leonardo Carmo de Andrade
Munford, Veridiana
Belizário, José Ernesto
Menck, Carlos Frederico Martins
author_role author
author2 Garcia, Camila Carrião Machado
Vieira, Debora Braga
Quinet, Annabel
Lima, Leonardo Carmo de Andrade
Munford, Veridiana
Belizário, José Ernesto
Menck, Carlos Frederico Martins
author2_role author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Rocha, Clarissa Ribeiro Reily
Garcia, Camila Carrião Machado
Vieira, Debora Braga
Quinet, Annabel
Lima, Leonardo Carmo de Andrade
Munford, Veridiana
Belizário, José Ernesto
Menck, Carlos Frederico Martins
description Malignant glioma is a severe type of brain tumor with a poor prognosis and few options for therapy. The main chemotherapy protocol for this type of tumor is based on temozolomide (TMZ), albeit with limited success. Cisplatin is widely used to treat several types of tumor and, in association with TMZ, is also used to treat recurrent glioma. However, several mechanisms of cellular resistance to cisplatin restrict therapy efficiency. In that sense, enhanced DNA repair, high glutathione levels and functional p53 have a critical role on cisplatin resistance. In this work, we explored several mechanisms of cisplatin resistance in human glioma. We showed that cellular survival was independent of the p53 status of those cells. In addition, in a host-cell reactivation assay using cisplatin-treated plasmid, we did not detect any difference in DNA repair capacity. We demonstrated that cisplatin-treated U138MG cells suffered fewer DNA double-strand breaks and DNA platination. Interestingly, the resistant cells carried higher levels of intracellular glutathione. Thus, preincubation with the glutathione inhibitor buthionine sulfoximine (BSO) induced massive cell death, whereas N-acetyl cysteine, a precursor of glutathione synthesis, improved the resistance to cisplatin treatment. In addition, BSO sensitized glioma cells to TMZ alone or in combination with cisplatin. Furthermore, using an in vivo model the combination of BSO, cisplatin and TMZ activated the caspase 3–7 apoptotic pathway. Remarkably, the combined treatment did not lead to severe side effects, while causing a huge impact on tumor progression. In fact, we noted a remarkable threefold increase in survival rate compared with other treatment regimens. Thus, the intracellular glutathione concentration is a potential molecular marker for cisplatin resistance in glioma, and the use of glutathione inhibitors, such as BSO, in association with cisplatin and TMZ seems a promising approach for the therapy of such devastating tumors.
publishDate 2014
dc.date.none.fl_str_mv 2014
2015-09-22T19:06:46Z
2015-09-22T19:06:46Z
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.uri.fl_str_mv ROCHA, C. R. R. et al. Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo. Cell Death & Disease, v. 5, p. e1505, 2014. Disponível em: <https://www.nature.com/articles/cddis2014465>. Acesso em: 22 maio 2015.
2041-4889
http://www.repositorio.ufop.br/handle/123456789/5611
https://doi.org/10.1038/cddis.2014.465
identifier_str_mv ROCHA, C. R. R. et al. Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo. Cell Death & Disease, v. 5, p. e1505, 2014. Disponível em: <https://www.nature.com/articles/cddis2014465>. Acesso em: 22 maio 2015.
2041-4889
url http://www.repositorio.ufop.br/handle/123456789/5611
https://doi.org/10.1038/cddis.2014.465
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
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dc.source.none.fl_str_mv reponame:Repositório Institucional da UFOP
instname:Universidade Federal de Ouro Preto (UFOP)
instacron:UFOP
instname_str Universidade Federal de Ouro Preto (UFOP)
instacron_str UFOP
institution UFOP
reponame_str Repositório Institucional da UFOP
collection Repositório Institucional da UFOP
repository.name.fl_str_mv Repositório Institucional da UFOP - Universidade Federal de Ouro Preto (UFOP)
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