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Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species
BACKGROUND: Metals including iron, copper and zinc are essential for physiological processes yet can be toxic at high concentrations. However the role of these metals in the progression of cancer is not well defined. Here we study the anti-tumor activity of the metal chelator, TPEN, and define its m...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223620/ https://www.ncbi.nlm.nih.gov/pubmed/25047035 http://dx.doi.org/10.1186/1471-2407-14-527 |
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author | Fatfat, Maamoun Merhi, Raghida Abou Rahal, Omar Stoyanovsky, Detcho A Zaki, Angela Haidar, Hazar Kagan, Valerian E Gali-Muhtasib, Hala Machaca, Khaled |
author_facet | Fatfat, Maamoun Merhi, Raghida Abou Rahal, Omar Stoyanovsky, Detcho A Zaki, Angela Haidar, Hazar Kagan, Valerian E Gali-Muhtasib, Hala Machaca, Khaled |
author_sort | Fatfat, Maamoun |
collection | PubMed |
description | BACKGROUND: Metals including iron, copper and zinc are essential for physiological processes yet can be toxic at high concentrations. However the role of these metals in the progression of cancer is not well defined. Here we study the anti-tumor activity of the metal chelator, TPEN, and define its mechanism of action. METHODS: Multiple approaches were employed, including cell viability, cell cycle analysis, multiple measurements of apoptosis, and mitochondrial function. In addition we measured cellular metal contents and employed EPR to record redox cycling of TPEN–metal complexes. Mouse xenografts were also performed to test the efficacy of TPEN in vivo. RESULTS: We show that metal chelation using TPEN (5μM) selectively induces cell death in HCT116 colon cancer cells without affecting the viability of non-cancerous colon or intestinal cells. Cell death was associated with increased levels of reactive oxygen species (ROS) and was inhibited by antioxidants and by prior chelation of copper. Interestingly, HCT116 cells accumulate copper to 7-folds higher levels than normal colon cells, and the TPEN-copper complex engages in redox cycling to generate hydroxyl radicals. Consistently, TPEN exhibits robust anti-tumor activity in vivo in colon cancer mouse xenografts. CONCLUSION: Our data show that TPEN induces cell death by chelating copper to produce TPEN-copper complexes that engage in redox cycling to selectively eliminate colon cancer cells. |
format | Online Article Text |
id | pubmed-4223620 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-42236202014-11-08 Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species Fatfat, Maamoun Merhi, Raghida Abou Rahal, Omar Stoyanovsky, Detcho A Zaki, Angela Haidar, Hazar Kagan, Valerian E Gali-Muhtasib, Hala Machaca, Khaled BMC Cancer Research Article BACKGROUND: Metals including iron, copper and zinc are essential for physiological processes yet can be toxic at high concentrations. However the role of these metals in the progression of cancer is not well defined. Here we study the anti-tumor activity of the metal chelator, TPEN, and define its mechanism of action. METHODS: Multiple approaches were employed, including cell viability, cell cycle analysis, multiple measurements of apoptosis, and mitochondrial function. In addition we measured cellular metal contents and employed EPR to record redox cycling of TPEN–metal complexes. Mouse xenografts were also performed to test the efficacy of TPEN in vivo. RESULTS: We show that metal chelation using TPEN (5μM) selectively induces cell death in HCT116 colon cancer cells without affecting the viability of non-cancerous colon or intestinal cells. Cell death was associated with increased levels of reactive oxygen species (ROS) and was inhibited by antioxidants and by prior chelation of copper. Interestingly, HCT116 cells accumulate copper to 7-folds higher levels than normal colon cells, and the TPEN-copper complex engages in redox cycling to generate hydroxyl radicals. Consistently, TPEN exhibits robust anti-tumor activity in vivo in colon cancer mouse xenografts. CONCLUSION: Our data show that TPEN induces cell death by chelating copper to produce TPEN-copper complexes that engage in redox cycling to selectively eliminate colon cancer cells. BioMed Central 2014-07-21 /pmc/articles/PMC4223620/ /pubmed/25047035 http://dx.doi.org/10.1186/1471-2407-14-527 Text en Copyright © 2014 Fatfat et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Fatfat, Maamoun Merhi, Raghida Abou Rahal, Omar Stoyanovsky, Detcho A Zaki, Angela Haidar, Hazar Kagan, Valerian E Gali-Muhtasib, Hala Machaca, Khaled Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species |
title | Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species |
title_full | Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species |
title_fullStr | Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species |
title_full_unstemmed | Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species |
title_short | Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species |
title_sort | copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223620/ https://www.ncbi.nlm.nih.gov/pubmed/25047035 http://dx.doi.org/10.1186/1471-2407-14-527 |
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