Cargando…
Withaferin A-Induced Apoptosis in Human Breast Cancer Cells Is Mediated by Reactive Oxygen Species
Withaferin A (WA), a promising anticancer constituent of Ayurvedic medicinal plant Withania somnifera, inhibits growth of MDA-MB-231 and MCF-7 human breast cancer cells in culture and MDA-MB-231 xenografts in vivo in association with apoptosis induction, but the mechanism of cell death is not fully...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154436/ https://www.ncbi.nlm.nih.gov/pubmed/21853114 http://dx.doi.org/10.1371/journal.pone.0023354 |
_version_ | 1782210016777863168 |
---|---|
author | Hahm, Eun-Ryeong Moura, Michelle B. Kelley, Eric E. Van Houten, Bennett Shiva, Sruti Singh, Shivendra V. |
author_facet | Hahm, Eun-Ryeong Moura, Michelle B. Kelley, Eric E. Van Houten, Bennett Shiva, Sruti Singh, Shivendra V. |
author_sort | Hahm, Eun-Ryeong |
collection | PubMed |
description | Withaferin A (WA), a promising anticancer constituent of Ayurvedic medicinal plant Withania somnifera, inhibits growth of MDA-MB-231 and MCF-7 human breast cancer cells in culture and MDA-MB-231 xenografts in vivo in association with apoptosis induction, but the mechanism of cell death is not fully understood. We now demonstrate, for the first time, that WA-induced apoptosis is mediated by reactive oxygen species (ROS) production due to inhibition of mitochondrial respiration. WA treatment caused ROS production in MDA-MB-231 and MCF-7 cells, but not in a normal human mammary epithelial cell line (HMEC). The HMEC was also resistant to WA-induced apoptosis. WA-mediated ROS production as well as apoptotic histone-associated DNA fragment release into the cytosol was significantly attenuated by ectopic expression of Cu,Zn-superoxide dismutase in both MDA-MB-231 and MCF-7 cells. ROS production resulting from WA exposure was accompanied by inhibition of oxidative phosphorylation and inhibition of complex III activity. Mitochondrial DNA-deficient Rho-0 variants of MDA-MB-231 and MCF-7 cells were resistant to WA-induced ROS production, collapse of mitochondrial membrane potential, and apoptosis compared with respective wild-type cells. WA treatment resulted in activation of Bax and Bak in MDA-MB-231 and MCF-7 cells, and SV40 immortalized embryonic fibroblasts derived from Bax and Bak double knockout mouse were significantly more resistant to WA-induced apoptosis compared with fibroblasts derived from wild-type mouse. In conclusion, the present study provides novel insight into the molecular circuitry of WA-induced apoptosis involving ROS production and activation of Bax/Bak. |
format | Online Article Text |
id | pubmed-3154436 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31544362011-08-18 Withaferin A-Induced Apoptosis in Human Breast Cancer Cells Is Mediated by Reactive Oxygen Species Hahm, Eun-Ryeong Moura, Michelle B. Kelley, Eric E. Van Houten, Bennett Shiva, Sruti Singh, Shivendra V. PLoS One Research Article Withaferin A (WA), a promising anticancer constituent of Ayurvedic medicinal plant Withania somnifera, inhibits growth of MDA-MB-231 and MCF-7 human breast cancer cells in culture and MDA-MB-231 xenografts in vivo in association with apoptosis induction, but the mechanism of cell death is not fully understood. We now demonstrate, for the first time, that WA-induced apoptosis is mediated by reactive oxygen species (ROS) production due to inhibition of mitochondrial respiration. WA treatment caused ROS production in MDA-MB-231 and MCF-7 cells, but not in a normal human mammary epithelial cell line (HMEC). The HMEC was also resistant to WA-induced apoptosis. WA-mediated ROS production as well as apoptotic histone-associated DNA fragment release into the cytosol was significantly attenuated by ectopic expression of Cu,Zn-superoxide dismutase in both MDA-MB-231 and MCF-7 cells. ROS production resulting from WA exposure was accompanied by inhibition of oxidative phosphorylation and inhibition of complex III activity. Mitochondrial DNA-deficient Rho-0 variants of MDA-MB-231 and MCF-7 cells were resistant to WA-induced ROS production, collapse of mitochondrial membrane potential, and apoptosis compared with respective wild-type cells. WA treatment resulted in activation of Bax and Bak in MDA-MB-231 and MCF-7 cells, and SV40 immortalized embryonic fibroblasts derived from Bax and Bak double knockout mouse were significantly more resistant to WA-induced apoptosis compared with fibroblasts derived from wild-type mouse. In conclusion, the present study provides novel insight into the molecular circuitry of WA-induced apoptosis involving ROS production and activation of Bax/Bak. Public Library of Science 2011-08-10 /pmc/articles/PMC3154436/ /pubmed/21853114 http://dx.doi.org/10.1371/journal.pone.0023354 Text en Hahm 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 Hahm, Eun-Ryeong Moura, Michelle B. Kelley, Eric E. Van Houten, Bennett Shiva, Sruti Singh, Shivendra V. Withaferin A-Induced Apoptosis in Human Breast Cancer Cells Is Mediated by Reactive Oxygen Species |
title | Withaferin A-Induced Apoptosis in Human Breast Cancer Cells Is Mediated by Reactive Oxygen Species |
title_full | Withaferin A-Induced Apoptosis in Human Breast Cancer Cells Is Mediated by Reactive Oxygen Species |
title_fullStr | Withaferin A-Induced Apoptosis in Human Breast Cancer Cells Is Mediated by Reactive Oxygen Species |
title_full_unstemmed | Withaferin A-Induced Apoptosis in Human Breast Cancer Cells Is Mediated by Reactive Oxygen Species |
title_short | Withaferin A-Induced Apoptosis in Human Breast Cancer Cells Is Mediated by Reactive Oxygen Species |
title_sort | withaferin a-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154436/ https://www.ncbi.nlm.nih.gov/pubmed/21853114 http://dx.doi.org/10.1371/journal.pone.0023354 |
work_keys_str_mv | AT hahmeunryeong withaferinainducedapoptosisinhumanbreastcancercellsismediatedbyreactiveoxygenspecies AT mouramichelleb withaferinainducedapoptosisinhumanbreastcancercellsismediatedbyreactiveoxygenspecies AT kelleyerice withaferinainducedapoptosisinhumanbreastcancercellsismediatedbyreactiveoxygenspecies AT vanhoutenbennett withaferinainducedapoptosisinhumanbreastcancercellsismediatedbyreactiveoxygenspecies AT shivasruti withaferinainducedapoptosisinhumanbreastcancercellsismediatedbyreactiveoxygenspecies AT singhshivendrav withaferinainducedapoptosisinhumanbreastcancercellsismediatedbyreactiveoxygenspecies |