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Effects of the antiproliferative cyclopentenone prostaglandin A1 on glutathione metabolism in human cancer cells in culture
Author(s) -
de Bittencourt Paulo Homem,
Miyasaka Célio K.,
Curi Rui,
Williams John F.
Publication year - 1998
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1080/15216549800203472
Subject(s) - cyclopentenone , glutathione , prostaglandin , metabolism , cancer , chemistry , glutathione metabolism , biochemistry , cancer research , endocrinology , pharmacology , medicine , biology , enzyme , stereochemistry
Homeostatic mechanisms for the maintenance of glutathione (GSH) are fundamental in the provision of a cellular defense against electrophilic/oxidant challenges. Cyclopentenone prostaglandins (CP‐PGs) are powerful antiproliferative endogenous substances that may act as electrophilic regulating compounds, by virtue of the presence of an α,β‐unsaturated carbonyl group in the cyclopentane ring. Nevertheless, differential resistance to CP‐PG cytotoxic/cytostatic effect has been reported in different cell types. It is reported that the activity/expression of γ‐glutamylcysteine synthetase (γ‐GCS, the rate‐limiting enzyme in GSH biosynthesis) can be inducibly activated by electrophiles, including CP‐PGs. The response of the human cancer strains HEp‐2 (larynx carcinoma) and HL‐60 (promyelocytic leukemia) cells to treatment with the CP‐PG PGA1 in culture was investigated by evaluating the time‐course of GSH synthesis and activity of enzymes of GSH metabolism, other than γ‐GCS, after PGA1 addition. HEp‐2 cells, being more resistant to PGA1 cytotoxic and cytostatic effects, have basal GSH levels that were 2.4‐fold higher than that of HL‐60 cells. The activities of GSH S‐transferase (GST), glutathione reductase (GSRd) and glutathione peroxidase (GSPx) are constitutively higher in HL‐60 cells than in HEp‐2 cells (respectively, 17.0‐, 28.5‐ and 12.3‐fold). When challenged with PGA1, both cell types exhibited a dose‐dependent rise in GSH content that was maximal 18 h after PGA1 addition and was preceded by a rise in GST and GSRd activities in both cell types (at 12 h). GSPx activity increased only in HEp‐2 (PGA1 evoked a 93.4%‐inhibition in HL‐60 cells). Moreover only HEp‐2 cells exhibited early capacity to enhance GSH content (1‐2 h just after PGA1 addition). These results and earlier data showing that leukemia cells are sensitive to CP‐PG treatment suggest that deficiencies in GSH metabolism may be strategic in therapeutic approaches to the treatment of human leukemias.