Arsenic trioxide and auranofin inhibit selenoprotein synthesis: implications for chemotherapy for acute promyelocytic leukaemia
Abbreviated Journal Title
Br. J. Pharmacol.
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
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.
British Journal of Pharmacology
"Arsenic trioxide and auranofin inhibit selenoprotein synthesis: implications for chemotherapy for acute promyelocytic leukaemia" (2008). Faculty Bibliography 2000s. 1045.