Mitochondrial electron transport is the cellular target of the oncology drug elesclomol.
Elesclomol is a first-in-class investigational drug currently undergoing clinical evaluation as a novel cancer therapeutic. The potent antitumor activity of the compound results from the elevation of reactive oxygen species (ROS) and oxidative stress to levels incompatible with cellular survival. Ho...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3256171?pdf=render |
| _version_ | 1811296258717908992 |
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| author | Ronald K Blackman Kahlin Cheung-Ong Marinella Gebbia David A Proia Suqin He Jane Kepros Aurelie Jonneaux Philippe Marchetti Jerome Kluza Patricia E Rao Yumiko Wada Guri Giaever Corey Nislow |
| author_facet | Ronald K Blackman Kahlin Cheung-Ong Marinella Gebbia David A Proia Suqin He Jane Kepros Aurelie Jonneaux Philippe Marchetti Jerome Kluza Patricia E Rao Yumiko Wada Guri Giaever Corey Nislow |
| author_sort | Ronald K Blackman |
| collection | DOAJ |
| description | Elesclomol is a first-in-class investigational drug currently undergoing clinical evaluation as a novel cancer therapeutic. The potent antitumor activity of the compound results from the elevation of reactive oxygen species (ROS) and oxidative stress to levels incompatible with cellular survival. However, the molecular target(s) and mechanism by which elesclomol generates ROS and subsequent cell death were previously undefined. The cellular cytotoxicity of elesclomol in the yeast S. cerevisiae appears to occur by a mechanism similar, if not identical, to that in cancer cells. Accordingly, here we used a powerful and validated technology only available in yeast that provides critical insights into the mechanism of action, targets and processes that are disrupted by drug treatment. Using this approach we show that elesclomol does not work through a specific cellular protein target. Instead, it targets a biologically coherent set of processes occurring in the mitochondrion. Specifically, the results indicate that elesclomol, driven by its redox chemistry, interacts with the electron transport chain (ETC) to generate high levels of ROS within the organelle and consequently cell death. Additional experiments in melanoma cells involving drug treatments or cells lacking ETC function confirm that the drug works similarly in human cancer cells. This deeper understanding of elesclomol's mode of action has important implications for the therapeutic application of the drug, including providing a rationale for biomarker-based stratification of patients likely to respond in the clinical setting. |
| first_indexed | 2024-04-13T05:45:50Z |
| format | Article |
| id | doaj.art-5e320c1365494d17bd927ce04f47a8c1 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T05:45:50Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-5e320c1365494d17bd927ce04f47a8c12022-12-22T02:59:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0171e2979810.1371/journal.pone.0029798Mitochondrial electron transport is the cellular target of the oncology drug elesclomol.Ronald K BlackmanKahlin Cheung-OngMarinella GebbiaDavid A ProiaSuqin HeJane KeprosAurelie JonneauxPhilippe MarchettiJerome KluzaPatricia E RaoYumiko WadaGuri GiaeverCorey NislowElesclomol is a first-in-class investigational drug currently undergoing clinical evaluation as a novel cancer therapeutic. The potent antitumor activity of the compound results from the elevation of reactive oxygen species (ROS) and oxidative stress to levels incompatible with cellular survival. However, the molecular target(s) and mechanism by which elesclomol generates ROS and subsequent cell death were previously undefined. The cellular cytotoxicity of elesclomol in the yeast S. cerevisiae appears to occur by a mechanism similar, if not identical, to that in cancer cells. Accordingly, here we used a powerful and validated technology only available in yeast that provides critical insights into the mechanism of action, targets and processes that are disrupted by drug treatment. Using this approach we show that elesclomol does not work through a specific cellular protein target. Instead, it targets a biologically coherent set of processes occurring in the mitochondrion. Specifically, the results indicate that elesclomol, driven by its redox chemistry, interacts with the electron transport chain (ETC) to generate high levels of ROS within the organelle and consequently cell death. Additional experiments in melanoma cells involving drug treatments or cells lacking ETC function confirm that the drug works similarly in human cancer cells. This deeper understanding of elesclomol's mode of action has important implications for the therapeutic application of the drug, including providing a rationale for biomarker-based stratification of patients likely to respond in the clinical setting.http://europepmc.org/articles/PMC3256171?pdf=render |
| spellingShingle | Ronald K Blackman Kahlin Cheung-Ong Marinella Gebbia David A Proia Suqin He Jane Kepros Aurelie Jonneaux Philippe Marchetti Jerome Kluza Patricia E Rao Yumiko Wada Guri Giaever Corey Nislow Mitochondrial electron transport is the cellular target of the oncology drug elesclomol. PLoS ONE |
| title | Mitochondrial electron transport is the cellular target of the oncology drug elesclomol. |
| title_full | Mitochondrial electron transport is the cellular target of the oncology drug elesclomol. |
| title_fullStr | Mitochondrial electron transport is the cellular target of the oncology drug elesclomol. |
| title_full_unstemmed | Mitochondrial electron transport is the cellular target of the oncology drug elesclomol. |
| title_short | Mitochondrial electron transport is the cellular target of the oncology drug elesclomol. |
| title_sort | mitochondrial electron transport is the cellular target of the oncology drug elesclomol |
| url | http://europepmc.org/articles/PMC3256171?pdf=render |
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