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Int. J. Cancer: 71, 246–250 (1997)
r 1997 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Publication de l’Union Internationale Contre le Cancer
THE CELL-SPECIFIC ANTI-PROLIFERATIVE EFFECT OF REDUCED
GLUTATHIONE IS MEDIATED BY g-GLUTAMYL TRANSPEPTIDASE-DEPENDENT
EXTRACELLULAR PRO-OXIDANT REACTIONS
Paola PEREGO1, Aldo PAOLICCHI2, Roberto TONGIANI2, Alfonso POMPELLA3, Patrizia TONARELLI2, Nives CARENINI1,
Simona ROMANELLI1 and Franco ZUNINO1*
1Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy
2Università degli Studi di Pisa, Pisa, Italy
3Istituto di Patologia Generale, Siena, Italy
We have shown earlier that extracellular GSH can exert a
cell-specific growth-inhibitory effect on human tumor cells. In
the present study, 2 human ovarian carcinoma cell lines
(A2780 and IGROV-1) were used to investigate the biochemical basis of the GSH growth-inhibitory effect. Whereas cells
were resistant, A2780 cells were sensitive to a 1 hr exposure
to GSH, as assessed by the growth inhibition assay. Analysis of
relevant GSH-dependent enzymes indicated that A2780 cells
had low level of GSH S-transferase, glutathione reductase
and g-glutamyl transpeptidase (g-GT) activities in comparison with those of IGROV-1 cells, and GSH peroxidase activity
was undetectable in A2780 cells. The GSH effect was reversed by catalase and by dithiothreitol, indicating the occurrence of oxidative phenomena resulting in the impairment of
critical cellular thiols. Indeed treatment of cells with H2O2
also resulted in growth inhibition, which was more marked in
A2780 cells. The g-glutamyl acceptor glycylglycine, a cosubstrate for g-GT, potentiated the growth-inhibitory effect
of GSH, which in contrast was decreased by the g-GT
inhibitors, serine-borate complex and acivicin, suggesting
that the production of reactive forms of oxygen (probably
H2O2) was mediated by cysteinyl-glycine after GSH hydrolysis. The results support that the growth-inhibitory effect of
low GSH concentration is the result of oxidative damage
related to extracellular GSH metabolism. Int. J. Cancer 71:246–
250, 1997.
r 1997 Wiley-Liss, Inc.
The intracellular tripeptide thiol glutathione (GSH) plays an
important role in a series of physiologic functions related to its
anti-oxidant properties, including modulation of the redox status of
cellular proteins, protection from oxidative stress and detoxication
of electrophilic compounds (Meister, 1994). GSH has been implicated in modulating tumor-cell sensitivity to ionizing radiation,
alkylating agents and platinum compounds (Meijer et al., 1990).
Indeed, tumor cell lines selected in vitro for resistance to cisplatin
or alkylating agents may have high levels of GSH or exhibit high
capacity for GSH synthesis (Godwin et al., 1992). However, the
exact mechanism by which GSH influences the cytotoxicity of
DNA-damaging agents has not been fully elucidated. Drug transport in resistant tumor cell lines over-expressing the multidrugresistance-associated protein MRP has been reported to be regulated by intracellular GSH levels (Versantvoort et al., 1995).
However, the relevance of alterations of GSH metabolism in the
development of clinical resistance remains uncertain, since a
marked increase in GSH levels is not a frequent event in human
tumors (Pratesi et al., 1995).
Exogenous GSH is currently considered a promising chemoprotector against cisplatin-induced nephrotoxicity and neurotoxicity,
and it does not decrease the cytotoxic and anti-tumor activity of the
platinum compound (Zunino et al., 1989; Hamers et al., 1993). A
striking observation of drug/GSH combination studies is a cellspecific anti-proliferative effect of GSH itself at pharmacologically
relevant concentrations (Zunino et al., 1993; Tedeschi et al., 1991).
A tumor growth-inhibitory effect of exogenous GSH has been
described (Novi, 1980; Cook et al., 1984; Karmali, 1984). In
particular, Novi (1980) found that GSH may prevent tumor growth
or cause tumor regression during aflatoxin-induced hepatocarcino-
genesis in rats, although others could not confirm such observations
(Neal and Legg, 1983). The cellular and molecular basis of the
anti-proliferative effects of GSH remains uncertain.
With the goal of investigating the mechanisms helping to
determine cellular response to exogenous GSH, we used 2 ovarian
carcinoma cell lines provided with differential response to the thiol.
On the basis of the data obtained, we propose that the growthinhibitory effect of exogenous GSH is mediated by oxidative
phenomena, and that the differential sensitivity of the studied cell
lines may be accounted for by their different characteristics in
GSH-centered anti-oxidant enzymatic activities.
MATERIAL AND METHODS
Cell lines
The 2 ovarian carcinoma cell lines used in the study, IGROV-1
and A2780 (Bénard et al., 1985; Behrens et al., 1987) originated
from untreated patients. They were cultured in RPMI-1640 medium without antibiotics, supplemented with 10% FCS.
Reagents
GSH was kindly supplied by Boehringer Mannheim (Milan,
Italy). Immediately before use, GSH was freshly dissolved in water
(30 mg/ml) and further diluted in saline. Oxidized glutathione
(GSSG), catalase, dithiothreitol (DTT) and glycylglycine were
purchased from Sigma (St. Louis, MO). Acivicin (NC-163501) was
provided by the NCI (Bethesda, MD).
Growth-inhibition assay
The anti-proliferative effects of GSH on human carcinoma cells
were assessed as described (Perego et al., 1996). Briefly, cells in
the logarithmic phase of growth were harvested and seeded in
duplicate into 6-well plates (960 mm2, Costar, Pleasanton, CA).
Then, 24 hr after seeding, a freshly prepared solution of GSH
and/or other compounds was added to the medium and cells were
incubated for 1 hr. The medium was replaced with fresh medium
and cells were harvested 72 hr after the exposure, and counted with
a Coulter counter (PBI Electronics, Luton, UK). IC50 is defined as
the inhibitory concentration causing 50% decrease of cell growth
compared with untreated control.
Activity of GSH-dependent enzymes
All enzymatic activities were assayed as described (Pratesi et al.,
1995). Frozen cell pellets were thawed and homogenized on ice in
0.05 M Tris-HCl buffer, pH 7.4, by 20 strokes of a tight-fitting
Contract grant sponsors: Associazione Italiana per la Ricerche sul Cancro,
Ministero della Sanitá, Consiglio Nazionale delle Ricerche (Finalized
Project ACRO).
*Correspondence to: Division of Experimental Oncology B, Istituto
Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. Fax: 39-2-2390764.
Received 5 August 1996; revised 13 November 1996
ANTI-PROLIFERATIVE EFFECT OF REDUCED GLUTATHIONE
247
Dounce homogenizer. Aliquots of crude homogenates were used
for the determination of g-GT activity with g-glutamyl-pnitroaniline and glycilglycine as substrates. The remaining cell
homogenate was centrifuged at 105,000 g for 60 min, and the
supernatants were used for the determination of GSH S-transferase,
GSH peroxidase, glutatione reductase and g-glutamylcysteine
synthetase. The results are expressed as nmol/min/mg protein, with
the exception of g-glutamylcysteine synthetase, which was expressed as µg of inorganic phosphate (Pi) produced/min/mg
protein.
RESULTS AND DISCUSSION
Growth-inhibitory effects of GSH were studied in 2 human
ovarian carcinoma cell lines after 1-hr exposure to GSH. The
dose-response curves (Fig. 1a) indicated that the A2780 line was
sensitive to GSH treatment in the concentration range 10 to 300
µg/ml. In contrast, IGROV-1 cells were insensitive to GSH. The
anti-proliferative effect was selectively shown with reduced GSH;
the oxidized form of the thiol (GSSG) was ineffective in a wide
range of concentrations (Fig. 1b). A peculiar feature of the A2780
cell response to GSH exposure was a biphasic profile, since strong
inhibition (up to 80%) was observed at 100 to 300 µg/ml GSH,
whereas higher concentrations were ineffective. The differential
effect in the 2 cell lines was not related to intracellular accumulation of GSH. In fact, following 1-hr exposure to a GSH concentration (100 µg/ml) causing growth inhibition in A2780 cells, the
intracellular non-protein thiol level was appreciably increased only
in IGROV-1 cells (Tedeschi et al., 1991). This increase is allegedly
explained by the markedly higher (approximately 5-fold) expression of g-GT in IGROV-1 than in A2780 cells (Table I). In fact, the
role of g-GT in favoring the cellular uptake of GSH precursor
amino acids is well established (Hanigan and Ricketts, 1993).
To investigate the biochemical basis of the varying effect of GSH
on the 2 ovarian carcinoma lines, an analysis of the GSHdependent enzyme activities in IGROV-1 and A2780 cells was
undertaken. As shown in Table I, IGROV-1 cells had GSH
S-transferase activity 3-fold higher than A2780 cells. Higher
activity was also found in IGROV-1 cells for the other analyzed
enzymes (GSH peroxidase, glutathione reductase and g-GT), with
the exception of g-glutamylcysteine synthetase, whose levels were
similar in the 2 cell lines. Most interestingly, GSH peroxidase
activity was undetectable in the GSH-sensitive A2780 cells,
suggesting that the growth-inhibitory effect of GSH in these cells
might be related to impairment of the cellular detoxication of
peroxides.
The fact that intracellular GSH content was not increased in
sensitive A2780 cells suggests that the anti-proliferative effect of
GSH is mediated by a cell-specific mechanism operating extracellularly, probably at the membrane level. Several lines of evidence
indicate that thiols, including GSH, can mediate the production of
reactive forms of oxygen, such as H2O2 (Rowley and Halliwell,
1982; Misra, 1974; Tien et al., 1982). We therefore examined the
sensitivity of the 2 ovarian carcinoma cell lines to hydrogen
peroxide, and indeed, as shown in Figure 2, A2780 cells appeared
to be markedly more sensitive to H2O2 (IC50 5 0.026 mM) than
IGROV-1 cells (IC50 5 0.14 mM). We thus investigated whether
the addition of the H2O2-metabolizing enzyme catalase might
protect against the cytotoxic effects of GSH in A2780 cells. When
A2780 cells were exposed to GSH in the presence of non-toxic
concentrations of catalase, no appreciable decrease of cell growth
was detected (Fig. 3a), indicating that the damage induced by GSH
was dependent on extracellular production of H2O2. It is in fact
known that the scavenging of H2O2 by catalase is restricted to the
extracellular space (Gelvan et al., 1995).
A major effect of reactive oxygen species, including H2O2, is the
oxidation of thiol groups into proteins (Suzuki et al., 1990). The
possible involvement of oxidation of cellular thiols in the growthinhibitory effect of GSH was therefore investigated by means of the
FIGURE 1 – Effect of reduced (GSH) (a) and oxidized glutathione
(GSSG) (b) on human ovarian carcinoma cell lines after 1-hr exposure.
Closed circles, A2780 cells; open circles, IGROV-1 cells. Each point
represents the average of 3 to 6 independent experiments. Vertical bars,
SD. When not indicated, SD was smaller than symbol size.
TABLE I – ACTIVITY OF GSH-DEPENDENT ENZYMES IN A2780 AND IGROV-1
HUMAN OVARIAN CARCINOMA CELLS1
Activity
S-transferase2
GSH
GSH peroxidase2
Glutathione reductase2
g-glutamylcysteine synthase3
g-glutamyl transpeptidase3
Cell lines
A2780
IGROV-1
75.30
nd
11.10
1.31
8.86
229.60
8.41
62.30
1.26
43.98
1A representative experiment is reported; SD average 10%.–2Results
are expressed as nmol/min/mg.–3Activity is expressed as µg of
Pi/min/mg protein.–nd, not detectable.
disulfide-reducing agent DTT. Indeed, as shown in Figure 3b, the
addition of sub-toxic concentrations of DTT (0.1 mM) was able to
suppress the GSH-induced growth inhibition in A2780 cells,
indicating that the effect is mediated by the oxidation of critical
thiols involved in cellular proliferation. In several other experimental models, the ability of H2O2 to modulate cell proliferation
through the oxidation of critical thiols, e.g., of transcription factors,
has been in fact documented (Guehmann et al., 1992; Hainaut and
Milner, 1993).
The biphasic dose-response curve obtained after exposure of
A2780 cells to GSH (Fig. 1a) was consistently observed with a
248
PEREGO ET AL.
FIGURE 2 – Growth-inhibitory effect of hydrogen peroxide on A2780
and IGROV-1 cells after 1-hr exposure. Closed circles, A2780 cells;
open circles, IGROV-1 cells. Data points are the average of 2
independent experiments. Vertical bars, SD.
FIGURE 3 – (a) Suppression of GSH-induced growth inhibition in
A2780 cells by catalase. (s) GSH alone; (d) GSH 1 500 U/ml
catalase; (S) GSH 1 100 U/ml catalase. The effect was measured by
growth-inhibition assay after 1-hr simultaneous exposure. Vertical bars,
SD. (b) Suppression of GSH-induced growth inhibition in A2780 cells by
dithiothreitol. (s) GSH alone; (n) GSH 1 0.1 mM DTT. SD, vertical
bars. When not indicated, SD was smaller than symbol size.
series of GSH-sensitive cell lines (Zunino et al., 1993). It is
therefore likely that, while at lower GSH concentrations a prooxidant, anti-proliferative effect (probably mediated by reactive
oxygen species) is operative, at higher GSH concentrations (in the
mM range) the intrinsic anti-oxidant potential of GSH can be
FIGURE 4 – Potentiation of GSH-induced growth inhibition in A2780
cells by the g-GT co-substrate, glycylglycine (simultaneous combination). (s) GSH alone; (d) GSH 1 glycylglycine (2 mM).
FIGURE 5 – Suppression of GSH-induced growth inhibition in
A2780 cells by the g-GT inhibitors (simultaneous combination). (a) GSH
alone (s); GSH 1 serine-borate complex, 1 mM (S) or 10 mM (d). (b)
GSH alone (s); GSH 1 acivicin, 30 µg/ml (S) or 100 µg/ml (d).
prevalent, thus counteracting its own growth-inhibitory effect.
Thus, a plausible explanation of the unusual dose-response curve is
the involvement of thiol products of GSH catabolism in promoting
oxidative damage at low GSH concentrations. This interpretation is
also consistent with a lack of cellular effect of GSSG. Indeed, the
GSH hydrolysis by isolated g-GT has been shown to favor the
production of reactive forms of oxygen through Fe31 reduction
mediated by cysteinyl-glycine produced by enzymatic reaction
ANTI-PROLIFERATIVE EFFECT OF REDUCED GLUTATHIONE
(Stark et al., 1988, 1993). In our cellular system sensitive to GSH,
the putative involvement of plasma-membrane g-GT activity in
mediating the GSH anti-proliferative effect was therefore investigated by using modulators of the enzyme activity in combination
with GSH. As shown in Figure 4, when glycylglycine, a g-glutamyl
acceptor known to accelerate g-GT activity (Huseby and Strömme,
1974), was combined with GSH, the growth-inhibitory effect of
GSH on A2780 cells was remarkably increased, in conditions
where glycylglycine did not affect cell growth per se. Conversely,
when g-GT activity was competitively inhibited with the serineborate complex (Tate and Meister, 1978), A2780 cells were
protected from the GSH inhibitory effect (Fig. 5a). Partial protection was also observed when the non-competitive inhibitor acivicin
was employed at sub-toxic levels (Fig. 5b). Taken together, these
results support the interpretation that the effect of GSH on A2780
cells is mediated by its g-GT-dependent metabolism. It is thus
conceivable that competitive inhibition exerted on g-GT by GSH
itself at high concentrations (Hanigan et al., 1994b) may contribute
to the biphasic effect of GSH.
In conclusion, the present study indicates that (i) GSH, despite
being a major and well-established factor of cellular anti-oxidant
defense systems, may exert a cell-specific growth-inhibitory effect
at an extracellular level; (ii) the effect is mediated by the formation
of reactive oxygen species, such as H2O2; and (iii) GSH metabolism by plasma-membrane g-GT activity potentiates the effect. The
molecular basis for the observed cell specificity of the GSH
growth-inhibitory effect probably lies in the differential arrays of
anti-oxidant enzymes displayed by the studied cell lines. In
particular, the marked depression of GSH peroxidase, glutathione
reductase and GSH S-transferase activity detected in A2780 cells
249
may help to explain the selective susceptibility of these cells to the
g-GT-mediated pro-oxidant effects of GSH. An alternative explanation may be that oxidative stress, however generated, may have
varying effects on the proliferative capacity of different cell lines,
depending on the cell-specific expression of oxidant-sensitive
membrane receptors and/or other members of the signal transduction chain (Van der Vliet and Bast, 1992). The present observations
in the A2780 ovarian carcinoma cell line are consistent with the
interpretation given for the mutagenicity and genotoxicity of GSH
in different biological systems (Ross et al., 1986; Thust and Bach,
1985). Again, such effects have been shown to involve the
production of reactive forms of oxygen and/or other radicals (Stark
et al., 1994) and to be potentiated by GSH metabolism mediated by
g-GT (Stark et al., 1988).
Finally, since GSH is often used in combination with cisplatin in
high-dose therapy of advanced ovarian cancer (Di Re et al., 1993),
a tumor frequently expressing high g-GT levels (Hanigan et al.,
1994a), the cell specificity of the g-GT-mediated GSH growthinhibitory effect may have important clinical implications. Identification of the cellular targets of oxidative damage caused by
extracellular GSH may be of considerable biologic significance in
elucidating the regulatory mechanisms of cell proliferation, and
may have implications for pharmacologic intervention.
ACKNOWLEDGEMENTS
This work was supported in part by grants from the Associazione
Italiana per la Ricerca sul Cancro, Ministero della Sanità, and the
Consiglio Nazionale delle Ricerche (Finalized Project ACRO). We
thank Ms. L. Zanesi and Ms. B. Johnston for editorial assistance.
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