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Resveratrol abrogates the Temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the Temozolomide-induced senescence in glioma cells

BACKGROUND: Temozolomide (TMZ) is the most widely used drug to treat glioblastoma (GBM), which is the most common and aggressive primary tumor of the Central Nervous System and one of the hardest challenges in oncotherapy. TMZ is an alkylating agent that induces autophagy, apoptosis and senescence i...

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Autores principales: Filippi-Chiela, Eduardo C, Thomé, Marcos Paulo, Bueno e Silva, Mardja Manssur, Pelegrini, Alessandra Luíza, Ledur, Pitia Flores, Garicochea, Bernardo, Zamin, Lauren L, Lenz, Guido
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635906/
https://www.ncbi.nlm.nih.gov/pubmed/23522185
http://dx.doi.org/10.1186/1471-2407-13-147
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author Filippi-Chiela, Eduardo C
Thomé, Marcos Paulo
Bueno e Silva, Mardja Manssur
Pelegrini, Alessandra Luíza
Ledur, Pitia Flores
Garicochea, Bernardo
Zamin, Lauren L
Lenz, Guido
author_facet Filippi-Chiela, Eduardo C
Thomé, Marcos Paulo
Bueno e Silva, Mardja Manssur
Pelegrini, Alessandra Luíza
Ledur, Pitia Flores
Garicochea, Bernardo
Zamin, Lauren L
Lenz, Guido
author_sort Filippi-Chiela, Eduardo C
collection PubMed
description BACKGROUND: Temozolomide (TMZ) is the most widely used drug to treat glioblastoma (GBM), which is the most common and aggressive primary tumor of the Central Nervous System and one of the hardest challenges in oncotherapy. TMZ is an alkylating agent that induces autophagy, apoptosis and senescence in GBM cells. However, therapy with TMZ increases survival after diagnosis only from 12 to 14.4 months, making the development of combined therapies to treat GBM fundamental. One candidate for GBM therapy is Resveratrol (Rsv), which has additive toxicity with TMZ in several glioma cells in vitro and in vivo. However, the mechanism of Rsv and TMZ additive toxicity, which is the aim of the present work, is not clear, especially concerning cell cycle dynamics and long term effects. METHODS: Glioma cell lines were treated with Rsv and TMZ, alone or in combinations, and the induction and the role of autophagy, apoptosis, cell cycle dynamics, protein expression and phosphorylation status were measured. We further evaluated the long term senescence induction and clonogenic capacity. RESULTS: As expected, temozolomide caused a G2 cell cycle arrest and extensive DNA damage response. Rsv did not reduced this response, even increasing pATM, pChk2 and gammaH2Ax levels, but abrogated the temozolomide-induced G2 arrest, increasing levels of cyclin B and pRb(S807/811) and reducing levels of pWee1(S642) and pCdk1(Y15). This suggests a cellular state of forced passage through G2 checkpoint despite large DNA damage, a scenario that may produce mitotic catastrophe. Indeed, the proportion of cells with high nuclear irregularity increased from 6 to 26% in 48 h after cotreatment. At a long term, a reduction in clonogenic capacity was observed, accompanied by a large induction of senescence. CONCLUSION: The presence of Rsv forces cells treated with TMZ through mitosis leading to mitotic catastrophe and senescence, reducing the clonogenic capacity of glioma cells and increasing the chronic effects of temozolomide.
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spelling pubmed-36359062013-04-26 Resveratrol abrogates the Temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the Temozolomide-induced senescence in glioma cells Filippi-Chiela, Eduardo C Thomé, Marcos Paulo Bueno e Silva, Mardja Manssur Pelegrini, Alessandra Luíza Ledur, Pitia Flores Garicochea, Bernardo Zamin, Lauren L Lenz, Guido BMC Cancer Research Article BACKGROUND: Temozolomide (TMZ) is the most widely used drug to treat glioblastoma (GBM), which is the most common and aggressive primary tumor of the Central Nervous System and one of the hardest challenges in oncotherapy. TMZ is an alkylating agent that induces autophagy, apoptosis and senescence in GBM cells. However, therapy with TMZ increases survival after diagnosis only from 12 to 14.4 months, making the development of combined therapies to treat GBM fundamental. One candidate for GBM therapy is Resveratrol (Rsv), which has additive toxicity with TMZ in several glioma cells in vitro and in vivo. However, the mechanism of Rsv and TMZ additive toxicity, which is the aim of the present work, is not clear, especially concerning cell cycle dynamics and long term effects. METHODS: Glioma cell lines were treated with Rsv and TMZ, alone or in combinations, and the induction and the role of autophagy, apoptosis, cell cycle dynamics, protein expression and phosphorylation status were measured. We further evaluated the long term senescence induction and clonogenic capacity. RESULTS: As expected, temozolomide caused a G2 cell cycle arrest and extensive DNA damage response. Rsv did not reduced this response, even increasing pATM, pChk2 and gammaH2Ax levels, but abrogated the temozolomide-induced G2 arrest, increasing levels of cyclin B and pRb(S807/811) and reducing levels of pWee1(S642) and pCdk1(Y15). This suggests a cellular state of forced passage through G2 checkpoint despite large DNA damage, a scenario that may produce mitotic catastrophe. Indeed, the proportion of cells with high nuclear irregularity increased from 6 to 26% in 48 h after cotreatment. At a long term, a reduction in clonogenic capacity was observed, accompanied by a large induction of senescence. CONCLUSION: The presence of Rsv forces cells treated with TMZ through mitosis leading to mitotic catastrophe and senescence, reducing the clonogenic capacity of glioma cells and increasing the chronic effects of temozolomide. BioMed Central 2013-03-22 /pmc/articles/PMC3635906/ /pubmed/23522185 http://dx.doi.org/10.1186/1471-2407-13-147 Text en Copyright © 2013 Filippi-Chiela et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Filippi-Chiela, Eduardo C
Thomé, Marcos Paulo
Bueno e Silva, Mardja Manssur
Pelegrini, Alessandra Luíza
Ledur, Pitia Flores
Garicochea, Bernardo
Zamin, Lauren L
Lenz, Guido
Resveratrol abrogates the Temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the Temozolomide-induced senescence in glioma cells
title Resveratrol abrogates the Temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the Temozolomide-induced senescence in glioma cells
title_full Resveratrol abrogates the Temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the Temozolomide-induced senescence in glioma cells
title_fullStr Resveratrol abrogates the Temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the Temozolomide-induced senescence in glioma cells
title_full_unstemmed Resveratrol abrogates the Temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the Temozolomide-induced senescence in glioma cells
title_short Resveratrol abrogates the Temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the Temozolomide-induced senescence in glioma cells
title_sort resveratrol abrogates the temozolomide-induced g2 arrest leading to mitotic catastrophe and reinforces the temozolomide-induced senescence in glioma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635906/
https://www.ncbi.nlm.nih.gov/pubmed/23522185
http://dx.doi.org/10.1186/1471-2407-13-147
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