Document Detail


Arsenic trioxide and auranofin inhibit selenoprotein synthesis: implications for chemotherapy for acute promyelocytic leukaemia.
MedLine Citation:
PMID:  18587442     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Arsenicals have been used medicinally for decades to treat both infectious disease and cancer. Arsenic trioxide (As2O3) is effective for treatment of acute promyelocytic leukaemia (APL), yet the mechanism of action of this drug is still widely debated. Recently, As2O3 was shown to inhibit the activity of the selenoenzyme thioredoxin reductase (TrxR). TrxR has been proposed to be required for selenium metabolism. The effect of inhibitors of TrxR on selenium metabolism has yet to be assessed. This study aims to determine whether chemotherapeutics that target selenocysteine within selenoenzymes may also affect the metabolism of selenium.
EXPERIMENTAL APPROACH: A lung cell line, A549, was used to assess the effect of TrxR inhibitors on selenium metabolism, using 75Se-selenite. The level of mRNA encoding cytosolic TrxR (TrxR1) was determined using real-time reverse transcriptase-PCR. TrxR activity was determined in whole-cell extracts.
KEY RESULTS: Exposure of cells to As2O3, arsenite or auranofin led to a concentration-dependent reduction of selenium metabolism into selenoproteins. Knockdown of TrxR1, using small inhibitory RNA, did not affect selenium metabolism. Exposure of cells to monomethylarsonic acid, a potent inhibitor of TrxR, did not alter selenium metabolism but did inhibit enzyme activity.
CONCLUSIONS AND IMPLICATIONS: As2O3 and auranofin block the metabolism of selenium in A549 cells. Because As2O3 is used to treat APL, our findings may reveal the mechanism of this therapeutic action and lead to further research targeting selenium metabolism to find novel chemotherapeutic agents for the treatment of APL.
Authors:
S Talbot; R Nelson; W T Self
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-04-21
Journal Detail:
Title:  British journal of pharmacology     Volume:  154     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-06-30     Completed Date:  2008-10-02     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  940-8     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / enzymology,  genetics,  metabolism*
Antineoplastic Agents / pharmacology*
Arsenicals / pharmacology*
Arsenites / pharmacology
Auranofin / pharmacology*
Cell Line, Tumor
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Humans
Leukemia, Promyelocytic, Acute / drug therapy*,  enzymology,  metabolism
Lung Neoplasms / enzymology,  genetics,  metabolism*
Oxides / pharmacology*
Protein Biosynthesis / drug effects
RNA Interference
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Selenium Radioisotopes
Selenoproteins / biosynthesis*
Sodium Compounds / pharmacology
Sodium Selenite / metabolism
Thioredoxin Reductase 1 / antagonists & inhibitors,  metabolism
Grant Support
ID/Acronym/Agency:
ES01434/ES/NIEHS NIH HHS; R15 ES014354/ES/NIEHS NIH HHS; R15 ES014354-01/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Arsenicals; 0/Arsenites; 0/Enzyme Inhibitors; 0/Oxides; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Selenium Radioisotopes; 0/Selenoproteins; 0/Sodium Compounds; 1327-53-3/arsenic trioxide; 3H04W2810V/Auranofin; 48OVY2OC72/sodium arsenite; EC 1.8.1.9/TXNRD1 protein, human; EC 1.8.1.9/Thioredoxin Reductase 1; HIW548RQ3W/Sodium Selenite; J37VJ5709S/monomethylarsonic acid
Comments/Corrections

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