Document Detail

The thioredoxin system mediates redox-induced cell death in human colon cancer cells: implications for the mechanism of action of anticancer agents.
MedLine Citation:
PMID:  18922898     Owner:  NLM     Status:  MEDLINE    
Anticancer agents act, at least in part, by inducing reactive oxygen and nitrogen species (RONS). We examined the redox effect on SW480 and HT-29 colon cancer cells of four anticancer compounds, arsenic trioxide, phosphoaspirin, phosphosulindac, and nitric oxide-donating aspirin (NO-ASA). All compounds inhibited the growth of both cell lines (IC(50), 10-90 micromol/L) and induced RONS detected by a general RONS molecular probe. NO-ASA, which induced at least four individual RONS (NO, H(2)O(2), superoxide anion, and peroxynitirte), induced apoptotic and necrotic cell death that was RONS-mediated (cell death paralleled RONS levels and was abrogated by N-acetyl cysteine but not by diphenylene iodonium, which displayed prooxidant activity and enhanced cell death). Nuclear factor-kappaB and mitogen-activated protein kinases were modulated by RONS. Thioredoxin-1 (Trx-1), an oxidoreductase involved in redox regulation, was heavily oxidized in response to RONS and mediated the growth inhibitory effect of the anticancer agents; knocking-down trx-1 expression by small interfering RNA abrogated cell death induced by them. These compounds also inhibited the activity of Trx reductase that reduces oxidized Trx-1, whereas the Trx reductase inhibitor aurothiomalate synergized with NO-ASA in the induction of cell death. Our findings indicate that the Trx system mediates to a large extent redox-induced cell death in response to anticancer agents. This mechanism of action may be shared by more anticancer agents and deserves further assessment as a candidate mechanism for the pharmacologic control of cancer.
Yu Sun; Basil Rigas
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  68     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-16     Completed Date:  2008-11-07     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8269-77     Citation Subset:  IM    
Department of Medicine, Division of Cancer Prevention, Stony Brook University, Stony Brook, New York 11794-5200, USA.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Arsenicals / pharmacology
Aspirin / analogs & derivatives,  pharmacology
Gold Sodium Thiomalate / pharmacology
HT29 Cells
MAP Kinase Kinase Kinase 5 / physiology
Mitogen-Activated Protein Kinases / metabolism
NF-kappa B / metabolism
Nitric Oxide Donors / pharmacology
Organophosphates / pharmacology
Oxidative Stress
Oxides / pharmacology
Reactive Nitrogen Species / metabolism
Reactive Oxygen Species / metabolism
Thioredoxin-Disulfide Reductase / antagonists & inhibitors
Thioredoxins / physiology*
Grant Support
R01 CA092423/CA/NCI NIH HHS; R01 CA092423/CA/NCI NIH HHS; R01 CA101019/CA/NCI NIH HHS; R01 CA10101902/CA/NCI NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/Arsenicals; 0/NF-kappa B; 0/Nitric Oxide Donors; 0/Organophosphates; 0/Oxides; 0/Reactive Nitrogen Species; 0/Reactive Oxygen Species; 0/phosphoaspirin; 12244-57-4/Gold Sodium Thiomalate; 1327-53-3/arsenic trioxide; 50-78-2/Aspirin; 52500-60-4/Thioredoxins; EC Reductase; EC Protein Kinases; EC Kinase Kinase Kinase 5; EC protein, human

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