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Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia
By comparing imatinib-sensitive and -resistant chronic myeloid leukemia (CML) cell models, we investigated the molecular mechanisms by which tetrahydrobenzimidazole derivative TMQ0153 triggered caspase-dependent apoptosis at low concentrations accompanied by loss of mitochondrial membrane potential...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007439/ https://www.ncbi.nlm.nih.gov/pubmed/32034134 http://dx.doi.org/10.1038/s41419-020-2304-8 |
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author | Song, Sungmi Lee, Jin-Young Ermolenko, Ludmila Mazumder, Aloran Ji, Seungwon Ryu, Heeju Kim, HyeJin Kim, Dong-Wook Lee, Jung Weon Dicato, Mario Christov, Christo Schnekenburger, Michael Cerella, Claudia Gérard, Déborah Orlikova-Boyer, Barbora Al-Mourabit, Ali Diederich, Marc |
author_facet | Song, Sungmi Lee, Jin-Young Ermolenko, Ludmila Mazumder, Aloran Ji, Seungwon Ryu, Heeju Kim, HyeJin Kim, Dong-Wook Lee, Jung Weon Dicato, Mario Christov, Christo Schnekenburger, Michael Cerella, Claudia Gérard, Déborah Orlikova-Boyer, Barbora Al-Mourabit, Ali Diederich, Marc |
author_sort | Song, Sungmi |
collection | PubMed |
description | By comparing imatinib-sensitive and -resistant chronic myeloid leukemia (CML) cell models, we investigated the molecular mechanisms by which tetrahydrobenzimidazole derivative TMQ0153 triggered caspase-dependent apoptosis at low concentrations accompanied by loss of mitochondrial membrane potential (MMP) and increase of cytosolic free Ca(2+) levels. Interestingly, at higher concentrations, TMQ0153 induced necroptotic cell death with accumulation of ROS, both preventable by N-acetyl-L-cysteine (NAC) pretreatment. At necroptosis-inducing concentrations, we observed increased ROS and decreased ATP and GSH levels, concomitant with protective autophagy induction. Inhibitors such as bafilomycin A1 (baf-A1) and siRNA against beclin 1 abrogated autophagy, sensitized CML cells against TMQ0153 and enhanced necroptotic cell death. Importantly, TMQ153-induced necrosis led to cell surface exposure of calreticulin (CRT) and ERp57 as well as the release of extracellular ATP and high mobility group box (HMGB1) demonstrating the capacity of this compound to release immunogenic cell death (ICD) markers. We validated the anti-cancer potential of TMQ0153 by in vivo inhibition of K562 microtumor formation in zebrafish. Taken together, our findings provide evidence that cellular stress and redox modulation by TMQ0153 concentration-dependently leads to different cell death modalities including controlled necrosis in CML cell models. |
format | Online Article Text |
id | pubmed-7007439 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70074392020-02-10 Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia Song, Sungmi Lee, Jin-Young Ermolenko, Ludmila Mazumder, Aloran Ji, Seungwon Ryu, Heeju Kim, HyeJin Kim, Dong-Wook Lee, Jung Weon Dicato, Mario Christov, Christo Schnekenburger, Michael Cerella, Claudia Gérard, Déborah Orlikova-Boyer, Barbora Al-Mourabit, Ali Diederich, Marc Cell Death Dis Article By comparing imatinib-sensitive and -resistant chronic myeloid leukemia (CML) cell models, we investigated the molecular mechanisms by which tetrahydrobenzimidazole derivative TMQ0153 triggered caspase-dependent apoptosis at low concentrations accompanied by loss of mitochondrial membrane potential (MMP) and increase of cytosolic free Ca(2+) levels. Interestingly, at higher concentrations, TMQ0153 induced necroptotic cell death with accumulation of ROS, both preventable by N-acetyl-L-cysteine (NAC) pretreatment. At necroptosis-inducing concentrations, we observed increased ROS and decreased ATP and GSH levels, concomitant with protective autophagy induction. Inhibitors such as bafilomycin A1 (baf-A1) and siRNA against beclin 1 abrogated autophagy, sensitized CML cells against TMQ0153 and enhanced necroptotic cell death. Importantly, TMQ153-induced necrosis led to cell surface exposure of calreticulin (CRT) and ERp57 as well as the release of extracellular ATP and high mobility group box (HMGB1) demonstrating the capacity of this compound to release immunogenic cell death (ICD) markers. We validated the anti-cancer potential of TMQ0153 by in vivo inhibition of K562 microtumor formation in zebrafish. Taken together, our findings provide evidence that cellular stress and redox modulation by TMQ0153 concentration-dependently leads to different cell death modalities including controlled necrosis in CML cell models. Nature Publishing Group UK 2020-02-07 /pmc/articles/PMC7007439/ /pubmed/32034134 http://dx.doi.org/10.1038/s41419-020-2304-8 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Song, Sungmi Lee, Jin-Young Ermolenko, Ludmila Mazumder, Aloran Ji, Seungwon Ryu, Heeju Kim, HyeJin Kim, Dong-Wook Lee, Jung Weon Dicato, Mario Christov, Christo Schnekenburger, Michael Cerella, Claudia Gérard, Déborah Orlikova-Boyer, Barbora Al-Mourabit, Ali Diederich, Marc Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia |
title | Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia |
title_full | Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia |
title_fullStr | Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia |
title_full_unstemmed | Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia |
title_short | Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia |
title_sort | tetrahydrobenzimidazole tmq0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007439/ https://www.ncbi.nlm.nih.gov/pubmed/32034134 http://dx.doi.org/10.1038/s41419-020-2304-8 |
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