Pih. Debittencourt et al., EFFECTS OF THE ANTIPROLIFERATIVE CYCLOPENTENONE PROSTAGLANDIN A(1) ONGLUTATHIONE METABOLISM IN HUMAN CANCER-CELLS IN CULTURE, Biochemistry and molecular biology international, 45(6), 1998, pp. 1255-1264
Homeostatic mechanisms for the maintenance of glutathione (GSH) are fu
ndamental in the provision of a cellular defense against electrophilic
/oxidant challenges. Cyclopentenone prostaglandins (CP-PGs) are powerf
ul antiproliferative endogenous substances that may act as electrophil
ic regulating compounds, by virtue of the presence of an alpha,beta-un
saturated carbonyl group in the cyclopentane ring. Nevertheless, diffe
rential resistance to CP-PG cytotoxic/cytostatic effect has been repor
ted in different cell types. It is reported that the activity/expressi
on of gamma-glutamylcysteine synthetase (gamma-GCS, the rate-limiting
enzyme in GSH biosynthesis) can be inducibly activated by electrophile
s, including CP-PGs. The response of the human cancer strains HEp-2 (l
arynx carcinoma) and HL-60 (promyelocytic leukemia) cells to treatment
with the CP-PG PGA(1) in culture was investigated by evaluating the t
ime-course of GSH synthesis and activity of enzymes of GSH metabolism,
other than gamma-GCS, after PGA(1) addition. HEp-2 cells, being more
resistant to PGA(1) cytotoxic and cytostatic effects, have basal GSH l
evels that were 2.4-fold higher than that of HL-60 cells. The activiti
es of GSH S-transferase (GST), glutathione reductase (GSRd) and glutat
hione peroxidase (GSPx) are constitutively higher in HL-60 cells than
in HEp-2 cells (respectively, 17.0-, 28.5- and 12.3-fold). When challe
nged with PGA(1), both cell types exhibited a dose-dependent rise in G
SH content that was maximal 18 h after PGA(1) addition and was precede
d by a rise in GST and GSRd activities in both cell types (at 12 h). G
SPx activity increased only in HEp-2 (PGA(1) evoked a 93.4%-inhibition
in HL-60 cells). Moreover only HEp-2 cells exhibited early capacity t
o enhance GSH content (1-2 h just after PGA(1) addition). These result
s and earlier data showing that leukemia cells are sensitive to CP-PG
treatment suggest that deficiencies in GSH metabolism may be strategic
al in therapeutic approaches to the treatment of human leukemias.