Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.
Autor(a) principal: | |
---|---|
Data de Publicação: | 2014 |
Outros Autores: | , , , , , , |
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. |
id |
UFOP_c66aa6eac7e81bbe5068f03ea07b8de3 |
---|---|
oai_identifier_str |
oai:repositorio.ufop.br:123456789/5611 |
network_acronym_str |
UFOP |
network_name_str |
Repositório Institucional da UFOP |
repository_id_str |
3233 |
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 |
dc.format.none.fl_str_mv |
application/pdf |
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) |
repository.mail.fl_str_mv |
repositorio@ufop.edu.br |
_version_ |
1813002864775135232 |