© 1997 by Oxford University Press
Journal Of The National Cancer Institute, Vol 89, 40-48, Copyright © 1997 by Oxford University Press
MO Ripple, WF Henry, RP Rago and G Wilding
BACKGROUND: Prostate cancer is a disease associated with aging. Also
commonly associated with increasing age is a shift in the prooxidant-
antioxidant balance of many tissues toward a more oxidative state, i.e.,
increased oxidative stress. We hypothesize that androgen exposure, which
has long been associated with the development of prostate cancer, may be a
means by which the prooxidant-antioxidant balance of prostate cells is
altered. PURPOSE: Using established prostate carcinoma cell lines, we
studied the effect of androgens on various parameters of oxidative state
(e.g., generation of hydrogen peroxide and hydroxyl radicals, lipid
peroxidation, and oxygen consumption) and antioxidant defense mechanisms
(e.g., the glutathione system and catalase). METHODS: The
androgen-responsive LNCaP and the androgen-independent DU145 prostate
carcinoma cell lines were exposed to 5 alpha-dihydrotestosterone (DHT) and
to the synthetic androgen R1881. The cellular proliferation responses were
measured by use of a fluorometric assay to quantitate the amount of DNA.
The generation of reactive oxygen species was measured by use of
2',7'-dichlorofluorescin diacetate, a dye that fluoresces in the presence
of hydrogen peroxide or hydroxyl radicals. Lipid peroxidation was
quantitated by use of a chromogen specific for malonaldehyde and
4-hydroxy-2(E)-nonenal. General mitochondrial activity was determined by
assaying 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) reduction. A Clark-type electrode was used to assess oxygen
consumption per cell. Intracellular glutathione concentrations and the
activities of catalase and gamma-glutamyl transpeptidase were measured
spectrophotometrically. All P values resulted from two-sided tests.
RESULTS: DHT at less than 1 to 100 nM (a concentration range encompassing
the physiologic levels of DHT considering all ages) and R1881 at 0.1-1 nM
concentrations were effective in inducing in LNCaP cells comparable
proliferative responses and changes in oxidative stress. In contrast,
neither DHT nor R1881 had any effect on the oxidative stress in DU145
cells. The mitochondrial activity in LNCaP cells, as measured by MTT
reduction, was significantly elevated above the levels of the untreated
controls by DHT (0.1-1000 nM) and R1881 (0.05-1 nM) (P < .001 in both).
Oxygen consumption and catalase activity were increased in LNCaP cells in
the presence of 1 nM R1881 by 60% and 40%, respectively, over the values in
the untreated control cells (P < .03 and P < .01, respectively). The
same concentration of R1881 resulted in a decrease in intracellular
glutathione concentrations and an increase in gamma-glutamyl transpeptidase
activity in LNCaP cells. Treatment with the oxidizing agents H2O2 and
menadione produced an increase in gamma-glutamyl transpeptidase activity in
LNCaP cells, whereas treatment with the antioxidant compound ascorbic acid
(100 mM) reduced the oxidative stress produced in LNCaP cells by 1 nM R1881
and completely blocked the gamma-glutamyl transpeptidase activity.
CONCLUSIONS: Physiologic levels of androgens are capable of increasing
oxidative stress in androgen- responsive LNCaP prostate carcinoma cells.
The evidence suggests that this result is due in part to increased
mitochondrial activity. Androgens also alter intracellular glutathione
levels and the activity of certain detoxification enzymes, such as
gamma-glutamyl transpeptidase, that are important for maintenance of the
cellular prooxidant-antioxidant balance.
ARTICLES
Prooxidant-antioxidant shift induced by androgen treatment of human prostate carcinoma cells
Department of Medicine, University of Wisconsin Comprehensive Cancer Center, Veteran's Administration Hospital, Madison, USA.
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