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Withaferin a-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species

Hahm, ER and Moura, MB and Kelley, EE and van Houten, B and Shiva, S and Singh, SV (2011) Withaferin a-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species. PLoS ONE, 6 (8).

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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. © 2011 Hahm et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Hahm, EReuh2@pitt.eduEUH2
Moura, MB
Kelley, EEekelley@pitt.eduEKELLEY
van Houten, Bbev15@pitt.eduBEV15
Shiva, Ssss43@pitt.eduSSS43
Singh, SVsvs2@pitt.eduSVS2
ContributionContributors NameEmailPitt UsernameORCID
Centers: Other Centers, Institutes, Offices, or Units > Pittsburgh Cancer Institute
Date: 15 August 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 8
DOI or Unique Handle: 10.1371/journal.pone.0023354
Schools and Programs: School of Medicine > Anesthesiology
School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
MeSH Headings: Adenosine Triphosphate--metabolism; Animals; Apoptosis--drug effects; Breast Neoplasms--enzymology; Breast Neoplasms--pathology; Cell Line, Tumor; Drug Resistance, Neoplasm--drug effects; Drug Screening Assays, Antitumor; Electron Transport Complex III--metabolism; Female; Humans; Mice; Oxidative Phosphorylation--drug effects; Protective Agents--pharmacology; Reactive Oxygen Species--metabolism; Superoxide Dismutase--metabolism; Withanolides--chemistry; Withanolides--pharmacology; bcl-2 Homologous Antagonist-Killer Protein--metabolism; bcl-2-Associated X Protein--metabolism; rho GTP-Binding Proteins--metabolism
Other ID: NLM PMC3154436
PubMed Central ID: PMC3154436
PubMed ID: 21853114
Date Deposited: 05 Sep 2012 18:51
Last Modified: 02 Feb 2019 21:55


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