Arsenic trioxide and auranofin inhibit selenoprotein synthesis: implications for chemotherapy for acute promyelocytic leukaemia.
OBJECTIVE
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.


METHODS
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.


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
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.
Talbot
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Department of Molecular Biology and Microbiology, Burnett College of Biomedical Science, University of Central Florida, Orlando, FL, USA.
Nelson
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Self
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D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D018053:Arsenites / Q000494:pharmacology; D001310:Auranofin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012644:Selenium Radioisotopes; D051140:Selenoproteins / Q000096:biosynthesis*; D017670:Sodium Compounds / Q000494:pharmacology; D018038:Sodium Selenite / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; D018053:Arsenites; D004791:Enzyme Inhibitors; D010087:Oxides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012644:Selenium Radioisotopes; D051140:Selenoproteins; D017670:Sodium Compounds; D001310:Auranofin; C017947:sodium arsenite; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D018038:Sodium Selenite; C020300:monomethylarsonic acid; D000077237:Arsenic Trioxide