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Winnett, Georgia; van Hagen, Daphne; Schrey, Michael

Prostaglandin J2 metabolites inhibit aromatase activity by redox‐sensitive mechanisms: Potential implications for breast cancer therapy

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  • Medientyp: E-Artikel
  • Titel: Prostaglandin J2 metabolites inhibit aromatase activity by redox‐sensitive mechanisms: Potential implications for breast cancer therapy
  • Beteiligte: Winnett, Georgia; van Hagen, Daphne; Schrey, Michael
  • Erschienen: Wiley, 2003
  • Erschienen in: International Journal of Cancer, 103 (2003) 5, Seite 600-605
  • Sprache: Englisch
  • DOI: 10.1002/ijc.10878
  • ISSN: 0020-7136; 1097-0215
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: AbstractThe mechanisms by which prostaglandin (PG)J2 metabolites inhibit tumorigenicity are poorly understood but may involve thiol reactivity or peroxisome proliferator‐activated receptor (PPAR)‐dependent pathways. Because aromatase is an important therapeutic target in breast cancer treatment, we have investigated the effect of PGJ2 metabolites on aromatase activity and evaluated a potential role for redox status during PGJ2 metabolite action. 15‐deoxy‐Δ12,14PGJ2 (15d‐PGJ2) and 9‐deoxy‐Δ9,1213,14‐dihydroPGD2 (Δ12PGJ2) caused dose‐dependent inhibition of both pre‐induced aromatase activity in human breast fibroblasts and MDA MB 231 breast cancer cells and of constitutive aromatase activity in JEG‐3 choriocarcinoma cells. Structure‐activity studies showed that this inhibition was mimicked by 4‐cyclopentene‐1,3‐dione but not by the PPARγ agonist troglitazone nor the eicosanoids PGE2 or arachidonic acid. The thiol oxidants diamide and H2O2 simulated the inhibitory action of 15d‐PGJ2 on aromatase activity, whereas the glutathione (GSH) repletor and antioxidant N‐acetyl‐cysteine (NAC) reversed these actions of 15d‐PGJ2 and H2O2 on aromatase. 15d‐PGJ2 also caused a direct dose‐dependent inhibition of aromatase activity in JEG‐3 cell sonicates, which was also reversed in the presence of GSH. Kinetic analysis of this 15d‐PGJ2‐induced inhibition of cell‐free aromatase indicated the involvement of a non‐competitive mechanism possibly resulting from direct thiol‐targeted alkylation of the enzyme. These redox‐sensitive, PPARγ‐independent actions of 15d‐PGJ2 on aromatase activity demonstrate a novel therapeutic potential for such cyclopentenone PGs in breast cancer treatment. © 2002 Wiley‐Liss, Inc.
  • Zugangsstatus: Freier Zugang