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Malabaricone-A Induces A Redox Imbalance That Mediates Apoptosis in U937 Cell Line
BACKGROUND: The ‘two-faced’ character of reactive oxygen species (ROS) plays an important role in cancer biology by acting both as secondary messengers in intracellular signaling cascades and sustaining the oncogenic phenotype of cancer cells, while on the other hand, it triggers an oxidative assaul...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349632/ https://www.ncbi.nlm.nih.gov/pubmed/22590637 http://dx.doi.org/10.1371/journal.pone.0036938 |
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author | Manna, Alak Saha, Piu Sarkar, Avijit Mukhopadhyay, Debanjan Bauri, Ajay K. Kumar, Deepak Das, Padma Chattopadhyay, Subrata Chatterjee, Mitali |
author_facet | Manna, Alak Saha, Piu Sarkar, Avijit Mukhopadhyay, Debanjan Bauri, Ajay K. Kumar, Deepak Das, Padma Chattopadhyay, Subrata Chatterjee, Mitali |
author_sort | Manna, Alak |
collection | PubMed |
description | BACKGROUND: The ‘two-faced’ character of reactive oxygen species (ROS) plays an important role in cancer biology by acting both as secondary messengers in intracellular signaling cascades and sustaining the oncogenic phenotype of cancer cells, while on the other hand, it triggers an oxidative assault that causes a redox imbalance translating into an apoptotic cell death. PRINCIPAL FINDINGS: Using a tetrazolium [{3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl}-2H-tetrazolium] based cell viability assay, we evaluated the cytotoxicity of a plant derived diarylnonanoid, malabaricone-A on leukemic cell lines U937 and MOLT-3. This cytotoxicity hinged on its ability to cause a redox imbalance via its ability to increase ROS, measured by flow cytometry using 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate and by decreasing glutathione peroxidase activity. This redox imbalance mediated apoptosis was evident by an increase in cytosolic [Ca(2+)], externalization of phosphatidyl serine as also depolarization of the mitochondrial membrane potential as measured by flow cytometry. There was concomitant peroxidation of cardiolipin, release of free cytochrome c to cytosol along with activation of caspases 9, 8 and 3. This led to cleavage of the DNA repair enzyme, poly (ADP-ribose) polymerase that caused DNA damage as proved by labeling with 4′,6-diamidino-2-phenylindole (DAPI); furthermore, terminal deoxy ribonucleotide transferase catalysed incorporation of deoxy uridine triphosphate confirmed DNA nicking and was accompanied by arrest of cell cycle progression. CONCLUSIONS: Taken together, compounds like MAL-A having pro-oxidant activity mediate their cytotoxicity in leukemic cells via induction of oxidative stress triggering a caspase dependent apoptosis. |
format | Online Article Text |
id | pubmed-3349632 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33496322012-05-15 Malabaricone-A Induces A Redox Imbalance That Mediates Apoptosis in U937 Cell Line Manna, Alak Saha, Piu Sarkar, Avijit Mukhopadhyay, Debanjan Bauri, Ajay K. Kumar, Deepak Das, Padma Chattopadhyay, Subrata Chatterjee, Mitali PLoS One Research Article BACKGROUND: The ‘two-faced’ character of reactive oxygen species (ROS) plays an important role in cancer biology by acting both as secondary messengers in intracellular signaling cascades and sustaining the oncogenic phenotype of cancer cells, while on the other hand, it triggers an oxidative assault that causes a redox imbalance translating into an apoptotic cell death. PRINCIPAL FINDINGS: Using a tetrazolium [{3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl}-2H-tetrazolium] based cell viability assay, we evaluated the cytotoxicity of a plant derived diarylnonanoid, malabaricone-A on leukemic cell lines U937 and MOLT-3. This cytotoxicity hinged on its ability to cause a redox imbalance via its ability to increase ROS, measured by flow cytometry using 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate and by decreasing glutathione peroxidase activity. This redox imbalance mediated apoptosis was evident by an increase in cytosolic [Ca(2+)], externalization of phosphatidyl serine as also depolarization of the mitochondrial membrane potential as measured by flow cytometry. There was concomitant peroxidation of cardiolipin, release of free cytochrome c to cytosol along with activation of caspases 9, 8 and 3. This led to cleavage of the DNA repair enzyme, poly (ADP-ribose) polymerase that caused DNA damage as proved by labeling with 4′,6-diamidino-2-phenylindole (DAPI); furthermore, terminal deoxy ribonucleotide transferase catalysed incorporation of deoxy uridine triphosphate confirmed DNA nicking and was accompanied by arrest of cell cycle progression. CONCLUSIONS: Taken together, compounds like MAL-A having pro-oxidant activity mediate their cytotoxicity in leukemic cells via induction of oxidative stress triggering a caspase dependent apoptosis. Public Library of Science 2012-05-10 /pmc/articles/PMC3349632/ /pubmed/22590637 http://dx.doi.org/10.1371/journal.pone.0036938 Text en Manna et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Manna, Alak Saha, Piu Sarkar, Avijit Mukhopadhyay, Debanjan Bauri, Ajay K. Kumar, Deepak Das, Padma Chattopadhyay, Subrata Chatterjee, Mitali Malabaricone-A Induces A Redox Imbalance That Mediates Apoptosis in U937 Cell Line |
title | Malabaricone-A Induces A Redox Imbalance That Mediates Apoptosis in U937 Cell Line |
title_full | Malabaricone-A Induces A Redox Imbalance That Mediates Apoptosis in U937 Cell Line |
title_fullStr | Malabaricone-A Induces A Redox Imbalance That Mediates Apoptosis in U937 Cell Line |
title_full_unstemmed | Malabaricone-A Induces A Redox Imbalance That Mediates Apoptosis in U937 Cell Line |
title_short | Malabaricone-A Induces A Redox Imbalance That Mediates Apoptosis in U937 Cell Line |
title_sort | malabaricone-a induces a redox imbalance that mediates apoptosis in u937 cell line |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349632/ https://www.ncbi.nlm.nih.gov/pubmed/22590637 http://dx.doi.org/10.1371/journal.pone.0036938 |
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