Phosphatidylinositol 3-kinase/AKT pathway inhibition by doxazosin promotes glioblastoma cells death, upregulation of p53 and triggers low neurotoxicity
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/224654 |
Resumo: | Glioblastoma is the most frequent and malignant brain tumor. Treatment includes chemotherapy with temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide, as well as the human glioblastoma cell line U138-MG. We investigated doxazosin’s (an antihypertensive drug) activity against glioblastoma cells (C6 and U138-MG) and its neurotoxicity on primary astrocytes and organoptypic hippocampal cultures. For this study, the following methods were used: citotoxicity assays, flow cytometry, western-blotting and confocal microscopy. We showed that doxazosin induces cell death on C6 and U138-MG cells. We observed that doxazosin’s effects on the PI3K/Akt pathway were similar as LY294002 (PI3K specific inhibitor). In glioblastoma cells treated with doxasozin, Akt levels were greatly reduced. Upon examination of activities of proteins downstream of Akt we observed upregulation of GSK-3β and p53. This led to cell proliferation inhibition, cell death induction via caspase-3 activation and cell cycle arrest at G0/G1 phase in glioblastoma cells. We used in this study Lapatinib, a tyrosine kinase inhibitor, as a comparison with doxazosin because they present similar chemical structure. We also tested the neurocitotoxicity of doxazosin in primary astrocytes and organotypic cultures and observed that doxazosin induced cell death on a small percentage of non-tumor cells. Aggressiveness of glioblastoma tumors and dismal prognosis require development of new treatment agents. This includes less toxic drugs, more selective towards tumor cells, causing less damage to the patient. Therefore, our results confirm the potential of doxazosin as an attractive therapeutic antiglioma agent. |
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Gaelzer, Mariana MaierCoelho, Bárbara ParanhosQuadros, Alice Hoffmann deHoppe, Juliana BenderTerra, Silvia ResendeGuerra, Maria Cristina Azambuja Barea da SilveiraUsach, VaninaGuma, Fátima Theresinha Costa RodriguesGoncalves, Carlos Alberto SaraivaSetton-Avruj, Patricia ClaraBattastini, Ana Maria OliveiraSalbego, Christianne Gazzana2021-07-28T04:40:24Z20161932-6203http://hdl.handle.net/10183/224654000996465Glioblastoma is the most frequent and malignant brain tumor. Treatment includes chemotherapy with temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide, as well as the human glioblastoma cell line U138-MG. We investigated doxazosin’s (an antihypertensive drug) activity against glioblastoma cells (C6 and U138-MG) and its neurotoxicity on primary astrocytes and organoptypic hippocampal cultures. For this study, the following methods were used: citotoxicity assays, flow cytometry, western-blotting and confocal microscopy. We showed that doxazosin induces cell death on C6 and U138-MG cells. We observed that doxazosin’s effects on the PI3K/Akt pathway were similar as LY294002 (PI3K specific inhibitor). In glioblastoma cells treated with doxasozin, Akt levels were greatly reduced. Upon examination of activities of proteins downstream of Akt we observed upregulation of GSK-3β and p53. This led to cell proliferation inhibition, cell death induction via caspase-3 activation and cell cycle arrest at G0/G1 phase in glioblastoma cells. We used in this study Lapatinib, a tyrosine kinase inhibitor, as a comparison with doxazosin because they present similar chemical structure. We also tested the neurocitotoxicity of doxazosin in primary astrocytes and organotypic cultures and observed that doxazosin induced cell death on a small percentage of non-tumor cells. Aggressiveness of glioblastoma tumors and dismal prognosis require development of new treatment agents. This includes less toxic drugs, more selective towards tumor cells, causing less damage to the patient. Therefore, our results confirm the potential of doxazosin as an attractive therapeutic antiglioma agent.application/pdfengPLoS ONE. San Francisco. Vol. 11, no. 4 (Apr. 2016), e0154612, 18 f.GlioblastomaDoxazossinaPhosphatidylinositol 3-kinase/AKT pathway inhibition by doxazosin promotes glioblastoma cells death, upregulation of p53 and triggers low neurotoxicityEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT000996465.pdf.txt000996465.pdf.txtExtracted Texttext/plain51042http://www.lume.ufrgs.br/bitstream/10183/224654/2/000996465.pdf.txtb231a8ae7e0585cc853c8592b2ff747bMD52ORIGINAL000996465.pdfTexto completo (inglês)application/pdf6190725http://www.lume.ufrgs.br/bitstream/10183/224654/1/000996465.pdff4dd223c585d867a7ea39d698f879752MD5110183/2246542023-01-20 06:01:26.147398oai:www.lume.ufrgs.br:10183/224654Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2023-01-20T08:01:26Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
Phosphatidylinositol 3-kinase/AKT pathway inhibition by doxazosin promotes glioblastoma cells death, upregulation of p53 and triggers low neurotoxicity |
title |
Phosphatidylinositol 3-kinase/AKT pathway inhibition by doxazosin promotes glioblastoma cells death, upregulation of p53 and triggers low neurotoxicity |
spellingShingle |
Phosphatidylinositol 3-kinase/AKT pathway inhibition by doxazosin promotes glioblastoma cells death, upregulation of p53 and triggers low neurotoxicity Gaelzer, Mariana Maier Glioblastoma Doxazossina |
title_short |
Phosphatidylinositol 3-kinase/AKT pathway inhibition by doxazosin promotes glioblastoma cells death, upregulation of p53 and triggers low neurotoxicity |
title_full |
Phosphatidylinositol 3-kinase/AKT pathway inhibition by doxazosin promotes glioblastoma cells death, upregulation of p53 and triggers low neurotoxicity |
title_fullStr |
Phosphatidylinositol 3-kinase/AKT pathway inhibition by doxazosin promotes glioblastoma cells death, upregulation of p53 and triggers low neurotoxicity |
title_full_unstemmed |
Phosphatidylinositol 3-kinase/AKT pathway inhibition by doxazosin promotes glioblastoma cells death, upregulation of p53 and triggers low neurotoxicity |
title_sort |
Phosphatidylinositol 3-kinase/AKT pathway inhibition by doxazosin promotes glioblastoma cells death, upregulation of p53 and triggers low neurotoxicity |
author |
Gaelzer, Mariana Maier |
author_facet |
Gaelzer, Mariana Maier Coelho, Bárbara Paranhos Quadros, Alice Hoffmann de Hoppe, Juliana Bender Terra, Silvia Resende Guerra, Maria Cristina Azambuja Barea da Silveira Usach, Vanina Guma, Fátima Theresinha Costa Rodrigues Goncalves, Carlos Alberto Saraiva Setton-Avruj, Patricia Clara Battastini, Ana Maria Oliveira Salbego, Christianne Gazzana |
author_role |
author |
author2 |
Coelho, Bárbara Paranhos Quadros, Alice Hoffmann de Hoppe, Juliana Bender Terra, Silvia Resende Guerra, Maria Cristina Azambuja Barea da Silveira Usach, Vanina Guma, Fátima Theresinha Costa Rodrigues Goncalves, Carlos Alberto Saraiva Setton-Avruj, Patricia Clara Battastini, Ana Maria Oliveira Salbego, Christianne Gazzana |
author2_role |
author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Gaelzer, Mariana Maier Coelho, Bárbara Paranhos Quadros, Alice Hoffmann de Hoppe, Juliana Bender Terra, Silvia Resende Guerra, Maria Cristina Azambuja Barea da Silveira Usach, Vanina Guma, Fátima Theresinha Costa Rodrigues Goncalves, Carlos Alberto Saraiva Setton-Avruj, Patricia Clara Battastini, Ana Maria Oliveira Salbego, Christianne Gazzana |
dc.subject.por.fl_str_mv |
Glioblastoma Doxazossina |
topic |
Glioblastoma Doxazossina |
description |
Glioblastoma is the most frequent and malignant brain tumor. Treatment includes chemotherapy with temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide, as well as the human glioblastoma cell line U138-MG. We investigated doxazosin’s (an antihypertensive drug) activity against glioblastoma cells (C6 and U138-MG) and its neurotoxicity on primary astrocytes and organoptypic hippocampal cultures. For this study, the following methods were used: citotoxicity assays, flow cytometry, western-blotting and confocal microscopy. We showed that doxazosin induces cell death on C6 and U138-MG cells. We observed that doxazosin’s effects on the PI3K/Akt pathway were similar as LY294002 (PI3K specific inhibitor). In glioblastoma cells treated with doxasozin, Akt levels were greatly reduced. Upon examination of activities of proteins downstream of Akt we observed upregulation of GSK-3β and p53. This led to cell proliferation inhibition, cell death induction via caspase-3 activation and cell cycle arrest at G0/G1 phase in glioblastoma cells. We used in this study Lapatinib, a tyrosine kinase inhibitor, as a comparison with doxazosin because they present similar chemical structure. We also tested the neurocitotoxicity of doxazosin in primary astrocytes and organotypic cultures and observed that doxazosin induced cell death on a small percentage of non-tumor cells. Aggressiveness of glioblastoma tumors and dismal prognosis require development of new treatment agents. This includes less toxic drugs, more selective towards tumor cells, causing less damage to the patient. Therefore, our results confirm the potential of doxazosin as an attractive therapeutic antiglioma agent. |
publishDate |
2016 |
dc.date.issued.fl_str_mv |
2016 |
dc.date.accessioned.fl_str_mv |
2021-07-28T04:40:24Z |
dc.type.driver.fl_str_mv |
Estrangeiro info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10183/224654 |
dc.identifier.issn.pt_BR.fl_str_mv |
1932-6203 |
dc.identifier.nrb.pt_BR.fl_str_mv |
000996465 |
identifier_str_mv |
1932-6203 000996465 |
url |
http://hdl.handle.net/10183/224654 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
PLoS ONE. San Francisco. Vol. 11, no. 4 (Apr. 2016), e0154612, 18 f. |
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info:eu-repo/semantics/openAccess |
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