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Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
Disruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac cells are disproportionately targeted by mitochondrial toxins resulting in a loss of cardiac function. An analysis of the effects...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316505/ https://www.ncbi.nlm.nih.gov/pubmed/32432547 http://dx.doi.org/10.7554/eLife.55845 |
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author | Stephenson, Zoe A Harvey, Robert F Pryde, Kenneth R Mistry, Sarah Hardy, Rachel E Serreli, Riccardo Chung, Injae Allen, Timothy EH Stoneley, Mark MacFarlane, Marion Fischer, Peter M Hirst, Judy Kellam, Barrie Willis, Anne E |
author_facet | Stephenson, Zoe A Harvey, Robert F Pryde, Kenneth R Mistry, Sarah Hardy, Rachel E Serreli, Riccardo Chung, Injae Allen, Timothy EH Stoneley, Mark MacFarlane, Marion Fischer, Peter M Hirst, Judy Kellam, Barrie Willis, Anne E |
author_sort | Stephenson, Zoe A |
collection | PubMed |
description | Disruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac cells are disproportionately targeted by mitochondrial toxins resulting in a loss of cardiac function. An analysis of the effects of mubritinib on cardiac cells showed that this drug did not inhibit HER2 as reported, but directly inhibits mitochondrial respiratory complex I, reducing cardiac-cell beat rate, with prolonged exposure resulting in cell death. We used a library of chemical variants of mubritinib and showed that modifying the 1H-1,2,3-triazole altered complex I inhibition, identifying the heterocyclic 1,3-nitrogen motif as the toxicophore. The same toxicophore is present in a second anti-cancer therapeutic carboxyamidotriazole (CAI) and we demonstrate that CAI also functions through complex I inhibition, mediated by the toxicophore. Complex I inhibition is directly linked to anti-cancer cell activity, with toxicophore modification ablating the desired effects of these compounds on cancer cell proliferation and apoptosis. |
format | Online Article Text |
id | pubmed-7316505 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-73165052020-06-29 Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I Stephenson, Zoe A Harvey, Robert F Pryde, Kenneth R Mistry, Sarah Hardy, Rachel E Serreli, Riccardo Chung, Injae Allen, Timothy EH Stoneley, Mark MacFarlane, Marion Fischer, Peter M Hirst, Judy Kellam, Barrie Willis, Anne E eLife Biochemistry and Chemical Biology Disruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac cells are disproportionately targeted by mitochondrial toxins resulting in a loss of cardiac function. An analysis of the effects of mubritinib on cardiac cells showed that this drug did not inhibit HER2 as reported, but directly inhibits mitochondrial respiratory complex I, reducing cardiac-cell beat rate, with prolonged exposure resulting in cell death. We used a library of chemical variants of mubritinib and showed that modifying the 1H-1,2,3-triazole altered complex I inhibition, identifying the heterocyclic 1,3-nitrogen motif as the toxicophore. The same toxicophore is present in a second anti-cancer therapeutic carboxyamidotriazole (CAI) and we demonstrate that CAI also functions through complex I inhibition, mediated by the toxicophore. Complex I inhibition is directly linked to anti-cancer cell activity, with toxicophore modification ablating the desired effects of these compounds on cancer cell proliferation and apoptosis. eLife Sciences Publications, Ltd 2020-05-20 /pmc/articles/PMC7316505/ /pubmed/32432547 http://dx.doi.org/10.7554/eLife.55845 Text en © 2020, Stephenson et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Stephenson, Zoe A Harvey, Robert F Pryde, Kenneth R Mistry, Sarah Hardy, Rachel E Serreli, Riccardo Chung, Injae Allen, Timothy EH Stoneley, Mark MacFarlane, Marion Fischer, Peter M Hirst, Judy Kellam, Barrie Willis, Anne E Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I |
title | Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I |
title_full | Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I |
title_fullStr | Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I |
title_full_unstemmed | Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I |
title_short | Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I |
title_sort | identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex i |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316505/ https://www.ncbi.nlm.nih.gov/pubmed/32432547 http://dx.doi.org/10.7554/eLife.55845 |
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