| A NADPH oxidase-dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells. | |
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MedLine Citation:
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PMID: 20233868 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cancer cells are usually under higher oxidative stress compared with normal cells. We hypothesize that introducing additional reactive oxygen species (ROS) insults or suppressing antioxidant capacity may selectively enhance cancer cell killing by oxidative stress-generating agents through stress overload or stress sensitization, whereas normal cells may be able to maintain redox homeostasis under exogenous ROS by adaptive response. Here, we show that parthenolide, a sesquiterpene lactone, selectively exhibits a radiosensitization effect on prostate cancer PC3 cells but not on normal prostate epithelial PrEC cells. Parthenolide causes oxidative stress in PC3 cells but not in PrEC cells, as determined by the oxidation of the ROS-sensitive probe H(2)DCFDA and intracellular reduced thiol and disulfide levels. In PC3 but not PrEC cells, parthenolide activates NADPH oxidase, leading to a decrease in the level of reduced thioredoxin, activation of phosphoinositide 3-kinase/Akt, and consequent FOXO3a phosphorylation, which results in the downregulation of FOXO3a targets antioxidant enzyme manganese superoxide dismutase and catalase. Importantly, when combined with radiation, parthenolide further increases ROS levels in PC3 cells whereas it decreases radiation-induced oxidative stress in PrEC cells, possibly by increasing reduced glutathione levels. Together, the results show that parthenolide selectively activates NADPH oxidase and mediates intense oxidative stress in prostate cancer cells by both increasing ROS generation and decreasing antioxidant defense capacity. The results support the concept of exploiting the intrinsic differences in the redox status of cancer cells and normal cells as targets for selective cancer killing. |
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Authors:
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Yulan Sun; Daret K St Clair; Yong Xu; Peter A Crooks; William H St Clair |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-03-16 |
Journal Detail:
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Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-02 Completed Date: 2010-05-03 Revised Date: 2013-05-29 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 2880-90 Citation Subset: IM |
Affiliation:
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Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Catalase
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metabolism Cell Line, Tumor Enzyme Activation / drug effects Forkhead Transcription Factors / metabolism Glutathione / metabolism Humans Male NADPH Oxidase / metabolism* Oncogene Protein v-akt / metabolism Oxidation-Reduction Oxidative Stress / drug effects Phosphatidylinositol 3-Kinases / metabolism Phosphorylation / drug effects Prostatic Neoplasms / drug therapy, enzymology*, radiotherapy Radiation-Sensitizing Agents / pharmacology* Sesquiterpenes / pharmacology* Signal Transduction Superoxide Dismutase / metabolism Thioredoxins / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA115801/CA/NCI NIH HHS; CA49797/CA/NCI NIH HHS; R01 CA115801-03/CA/NCI NIH HHS; R01 CA115801-05/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/FOXO3 protein, human; 0/Forkhead Transcription Factors; 0/Radiation-Sensitizing Agents; 0/Sesquiterpenes; 2RDB26I5ZB/parthenolide; 52500-60-4/Thioredoxins; 70-18-8/Glutathione; EC 1.11.1.6/Catalase; EC 1.15.1.1/Superoxide Dismutase; EC 1.6.3.1/NADPH Oxidase; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Oncogene Protein v-akt |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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