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Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines 2019, 7, 69

Temozolomide, a DNA methylating drug, is currently being used first-line in glioblastoma therapy. Although the mode of action of this so-called S(N)1 alkylating agent is well described, including the types of induced DNA damage triggering the DNA damage response and survival and death pathways, some...

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Autor principal: Kaina, Bernd
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966492/
https://www.ncbi.nlm.nih.gov/pubmed/31717973
http://dx.doi.org/10.3390/biomedicines7040090
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author Kaina, Bernd
author_facet Kaina, Bernd
author_sort Kaina, Bernd
collection PubMed
description Temozolomide, a DNA methylating drug, is currently being used first-line in glioblastoma therapy. Although the mode of action of this so-called S(N)1 alkylating agent is well described, including the types of induced DNA damage triggering the DNA damage response and survival and death pathways, some researchers expressed doubt that data mostly obtained by in vitro models can be translated into the in vivo situation. In experimental settings, high doses of the agent are often used, which are likely to activate responses triggered by base N-alkylations instead of O(6)-methylguanine (O(6)MeG), which is the primary cytotoxic lesion induced by low doses of temozolomide and other methylating drugs in O(6)-methylguanine-DNA methyltransferase (MGMT) repair incompetent cells. However, numerous studies provided compelling evidence that O(6)MeG is not only a mutagenic, but also a powerful toxic lesion inducing DNA double-strand breaks, apoptosis, autophagy and cellular senescence. MGMT, repairing the lesion through methyl group transfer, is a key node in protecting cells against all these effects and has a significant impact on patient’s survival following temozolomide therapy, supporting the notion that findings obtained on a molecular and cellular level can be translated to the therapeutic setting in vivo. This comment summarizes the current knowledge on O(6)MeG-triggered pathways, including dose dependence and the question of thresholds, and comes up with the conclusion that data obtained on cell lines using low dose protocols are relevant and apoptosis, autophagy and senescence are therapeutically important endpoints.
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spelling pubmed-69664922020-01-27 Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines 2019, 7, 69 Kaina, Bernd Biomedicines Comment Temozolomide, a DNA methylating drug, is currently being used first-line in glioblastoma therapy. Although the mode of action of this so-called S(N)1 alkylating agent is well described, including the types of induced DNA damage triggering the DNA damage response and survival and death pathways, some researchers expressed doubt that data mostly obtained by in vitro models can be translated into the in vivo situation. In experimental settings, high doses of the agent are often used, which are likely to activate responses triggered by base N-alkylations instead of O(6)-methylguanine (O(6)MeG), which is the primary cytotoxic lesion induced by low doses of temozolomide and other methylating drugs in O(6)-methylguanine-DNA methyltransferase (MGMT) repair incompetent cells. However, numerous studies provided compelling evidence that O(6)MeG is not only a mutagenic, but also a powerful toxic lesion inducing DNA double-strand breaks, apoptosis, autophagy and cellular senescence. MGMT, repairing the lesion through methyl group transfer, is a key node in protecting cells against all these effects and has a significant impact on patient’s survival following temozolomide therapy, supporting the notion that findings obtained on a molecular and cellular level can be translated to the therapeutic setting in vivo. This comment summarizes the current knowledge on O(6)MeG-triggered pathways, including dose dependence and the question of thresholds, and comes up with the conclusion that data obtained on cell lines using low dose protocols are relevant and apoptosis, autophagy and senescence are therapeutically important endpoints. MDPI 2019-11-11 /pmc/articles/PMC6966492/ /pubmed/31717973 http://dx.doi.org/10.3390/biomedicines7040090 Text en © 2019 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Comment
Kaina, Bernd
Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines 2019, 7, 69
title Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines 2019, 7, 69
title_full Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines 2019, 7, 69
title_fullStr Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines 2019, 7, 69
title_full_unstemmed Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines 2019, 7, 69
title_short Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy. Comment on Strobel et al., Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines 2019, 7, 69
title_sort temozolomide in glioblastoma therapy: role of apoptosis, senescence and autophagy. comment on strobel et al., temozolomide and other alkylating agents in glioblastoma therapy. biomedicines 2019, 7, 69
topic Comment
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966492/
https://www.ncbi.nlm.nih.gov/pubmed/31717973
http://dx.doi.org/10.3390/biomedicines7040090
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