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The thiosemicarbazone Me(2)NNMe(2) induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition
Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted su...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189190/ https://www.ncbi.nlm.nih.gov/pubmed/30323190 http://dx.doi.org/10.1038/s41419-018-1102-z |
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author | Hager, Sonja Korbula, Katharina Bielec, Björn Grusch, Michael Pirker, Christine Schosserer, Markus Liendl, Lisa Lang, Magdalena Grillari, Johannes Nowikovsky, Karin Pape, Veronika F. S. Mohr, Thomas Szakács, Gergely Keppler, Bernhard K. Berger, Walter Kowol, Christian R. Heffeter, Petra |
author_facet | Hager, Sonja Korbula, Katharina Bielec, Björn Grusch, Michael Pirker, Christine Schosserer, Markus Liendl, Lisa Lang, Magdalena Grillari, Johannes Nowikovsky, Karin Pape, Veronika F. S. Mohr, Thomas Szakács, Gergely Keppler, Bernhard K. Berger, Walter Kowol, Christian R. Heffeter, Petra |
author_sort | Hager, Sonja |
collection | PubMed |
description | Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative Me(2)NNMe(2) differs from Triapine not only in its efficacy but also in its mode of action. Here we show that Me(2)NNMe(2)- (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of Me(2)NNMe(2) (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca(2+) and ER thiol redox homeostasis. Our findings indicate that compounds like Me(2)NNMe(2) are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis. |
format | Online Article Text |
id | pubmed-6189190 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-61891902018-10-16 The thiosemicarbazone Me(2)NNMe(2) induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition Hager, Sonja Korbula, Katharina Bielec, Björn Grusch, Michael Pirker, Christine Schosserer, Markus Liendl, Lisa Lang, Magdalena Grillari, Johannes Nowikovsky, Karin Pape, Veronika F. S. Mohr, Thomas Szakács, Gergely Keppler, Bernhard K. Berger, Walter Kowol, Christian R. Heffeter, Petra Cell Death Dis Article Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative Me(2)NNMe(2) differs from Triapine not only in its efficacy but also in its mode of action. Here we show that Me(2)NNMe(2)- (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of Me(2)NNMe(2) (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca(2+) and ER thiol redox homeostasis. Our findings indicate that compounds like Me(2)NNMe(2) are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis. Nature Publishing Group UK 2018-10-15 /pmc/articles/PMC6189190/ /pubmed/30323190 http://dx.doi.org/10.1038/s41419-018-1102-z Text en © The Author(s) 2018 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 Hager, Sonja Korbula, Katharina Bielec, Björn Grusch, Michael Pirker, Christine Schosserer, Markus Liendl, Lisa Lang, Magdalena Grillari, Johannes Nowikovsky, Karin Pape, Veronika F. S. Mohr, Thomas Szakács, Gergely Keppler, Bernhard K. Berger, Walter Kowol, Christian R. Heffeter, Petra The thiosemicarbazone Me(2)NNMe(2) induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition |
title | The thiosemicarbazone Me(2)NNMe(2) induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition |
title_full | The thiosemicarbazone Me(2)NNMe(2) induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition |
title_fullStr | The thiosemicarbazone Me(2)NNMe(2) induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition |
title_full_unstemmed | The thiosemicarbazone Me(2)NNMe(2) induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition |
title_short | The thiosemicarbazone Me(2)NNMe(2) induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition |
title_sort | thiosemicarbazone me(2)nnme(2) induces paraptosis by disrupting the er thiol redox homeostasis based on protein disulfide isomerase inhibition |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189190/ https://www.ncbi.nlm.nih.gov/pubmed/30323190 http://dx.doi.org/10.1038/s41419-018-1102-z |
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