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

    Authors

    S. Talbot; R. Nelson;W. T. Self

    Comments

    Authors: contact us about adding a copy of your work at STARS@ucf.edu

    Abbreviated Journal Title

    Br. J. Pharmacol.

    Keywords

    arsenic trioxide; arsenite; auranofin; thioredoxin reductase; selenium; selenite; selenoprotein; acute promyelocytic leukaemia; TARGETING THIOREDOXIN REDUCTASE; CANCER-THERAPY; GOLD COMPOUNDS; GLUTATHIONE-PEROXIDASE; SELENIUM METABOLISM; EXOGENOUS SELENIUM; HYDROGEN-PEROXIDE; ARSINIUM ION; IN-VITRO; SELENOCYSTEINE; Pharmacology & Pharmacy

    Abstract

    Background and purpose: Arsenicals have been used medicinally for decades to treat both infectious disease and cancer. Arsenic trioxide (As(2)O(3)) is effective for treatment of acute promyelocytic leukaemia (APL), yet the mechanism of action of this drug is still widely debated. Recently, As(2)O(3) 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 (75)Se-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 As(2)O(3), 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: As(2)O(3) and auranofin block the metabolism of selenium in A549 cells. Because As(2)O(3) 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.

    Journal Title

    British Journal of Pharmacology

    Volume

    154

    Issue/Number

    5

    Publication Date

    1-1-2008

    Document Type

    Article

    Language

    English

    First Page

    940

    Last Page

    948

    WOS Identifier

    WOS:000257269400003

    ISSN

    0007-1188

    Share

    COinS