Prostaglandin J2 metabolites inhibit aromatase activity by redox-sensitive mechanisms: potential implications for breast cancer therapy.

Abstract

The mechanisms by which prostaglandin (PG)J(2) 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 PGJ(2) metabolites on aromatase activity and evaluated a potential role for redox status during PGJ(2) metabolite action. 15-deoxy-Delta(12,14)PGJ(2) (15d-PGJ(2)) and 9-deoxy-Delta(9,12)13,14-dihydroPGD(2) (Delta(12)PGJ(2)) 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 PPARgamma agonist troglitazone nor the eicosanoids PGE(2) or arachidonic acid. The thiol oxidants diamide and H(2)O(2) simulated the inhibitory action of 15d-PGJ(2) on aromatase activity, whereas the glutathione (GSH) repletor and antioxidant N-acetyl-cysteine (NAC) reversed these actions of 15d-PGJ(2) and H(2)O(2) on aromatase. 15d-PGJ(2) 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-PGJ(2)-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, PPARgamma-independent actions of 15d-PGJ(2) on aromatase activity demonstrate a novel therapeutic potential for such cyclopentenone PGs in breast cancer treatment.

• Authors: Georgia Winnett, Daphne van Hagen, Michael Schrey
• Journal: International journal of cancer (Int J Cancer) Vol. 103 Issue 5 Pg. 600-5 (Feb 20 2003) ISSN: 0020-7136 [Print] United States
• PMID: 12494466 (Publication Type: Journal Article)
• Copyright: Copyright 2002 Wiley-Liss, Inc.

Chemical References

• 15-deoxy-delta(12,14)-prostaglandin J2
• Antioxidants
• Aromatase Inhibitors
• Enzyme Inhibitors
• Receptors, Cytoplasmic and Nuclear
• Sulfhydryl Reagents
• Transcription Factors
• Hydrogen Peroxide
• Aromatase
• Glutathione
• Prostaglandin D2
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Antioxidants (pharmacology)
• Aromatase (metabolism)
• Aromatase Inhibitors
• Breast (metabolism)
• Breast Neoplasms (enzymology, prevention & control)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Female
• Fibroblasts (enzymology)
• Glutathione (metabolism)
• Humans
• Hydrogen Peroxide (pharmacology)
• Oxidation-Reduction
• Prostaglandin D2 (analogs & derivatives, pharmacology)
• Receptors, Cytoplasmic and Nuclear (agonists)
• Sulfhydryl Reagents (pharmacology)
• Transcription Factors (agonists)
• Tumor Cells, Cultured (drug effects)