Inhibition of Mammalian Thioredoxin Reductase by Some Flavonoids: Implications for Myricetin and Quercetin Anticancer Activity

Cancer Research - Tập 66 Số 8 - Trang 4410-4418 - 2006
Jun Lu1, Laura V. Papp1, Jianguo Fang1, Salvador Rodrı́guez-Nieto2, Boris Zhivotovsky2, Arne Holmgren1
11Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics and
22Division of Toxicology and Neurotoxicology, Institute of Environmental Medicine, Karolinska Institute, Sweden

Tóm tắt

Abstract The thioredoxin system, composed of thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH, exerts a wide range of activities in cellular redox control, antioxidant function, cell viability, and proliferation. Recently, the selenocysteine (Sec)-containing mammalian TrxR has emerged as a new target for anticancer drug development because TrxR and Trx are overexpressed in many aggressive tumors and the tumor cells seem to be more dependent on Trx system than normal cells. Here we have investigated the inhibition of mammalian TrxR by flavonoids which have been presumed to be cancer chemoprevention agents because of their antioxidant activities. Myricetin and quercetin were found to have strong inhibitory effects on mammalian TrxRs with IC50 values of 0.62 and 0.97 μmol/L, respectively. The inhibition was shown to be concentration, NADPH, and time dependent and involved an attack on the reduced COOH-terminal -Cys-Sec-Gly active site of TrxR. Oxygen-derived superoxide anions enhanced the inhibitory effect whereas anaerobic conditions attenuated inhibition. Spectral analysis suggested that the flavonols might perform their inhibitory effects via semiquinone radicals. Additionally, the flavonols had the potential to inhibit the growth of A549 cells with the same potency as inhibition of TrxR. TrxR activity in the cell lysates was reduced on treatment with myricetin >50 μmol/L, which coincided with the oxidization of Trx. The cell cycle was arrested in S phase by quercetin and an accumulation of cells in sub-G1 was observed in response to myricetin. Thus, the anticancer activity of quercetin and myricetin may be due to inhibition of TrxR, consequently inducing cell death. (Cancer Res 2006; 66(8): 4410-8)

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Cancer Research

Tập 66 Số 8

4410-4418

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