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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 2102-2111
Arsenic Trioxide Selectively Induces Acute Promyelocytic Leukemia Cell
Apoptosis Via a Hydrogen Peroxide-Dependent Pathway
By
Yongkui Jing,
Jie Dai,
Ruth M.E. Chalmers-Redman,
Willam G. Tatton, and
Samuel Waxman
From the Rochelle Belfer Chemotherapy Foundation Laboratory, Division
of Neoplastic Diseases, Department of Medicine, and the Department of
Neurology, Mount Sinai Medical Center, New York, NY.
 |
ABSTRACT |
Low concentrations of As2O3 ( 1 µmol/L)
induce long-lasting remission in patients with acute promyelocytic
leukemia (APL) without significant myelosuppressive side effects.
Several groups, including ours, have shown that 0.5 to 1 µmol/L
As2O3 induces apoptosis in APL-derived NB4
cells, whereas other leukemic cells are resistant to
As2O3 or undergo apoptosis only in response to greater than 2 µmol/L As2O3. In this report,
we show that the ability of As2O3 to induce
apoptosis in leukemic cells is dependent on the activity of the enzymes
that regulate cellular H2O2 content. Thus, NB4
cells have relatively low levels of glutathione peroxidase (GPx) and
catalase and have a constitutively higher H2O2
content than U937 monocytic leukemia cells. Glutathione-S-transferase  (GST), which is important for cellular efflux of
As2O3, is also low in NB4 cells. Moreover,
As2O3 further inhibits GPX activity and
increases cellular H2O2 content in NB4 but not
in U937 cells. Selenite pretreatment of NB4 cells increases the
activity of GPX, lowers cellular H2O2 levels,
and renders NB4 cells resistant to 1 µmol/L
As2O3. In contrast, concentrations of
As2O3 that alone are not capable of inducing
apoptosis in NB4 cells induce apoptosis in the presence of the GPx
inhibitor mercaptosuccinic acid. Similar effects are observed by
modulating the activity of catalase with its inhibitor, aminotriazol.
More important from a therapeutic point of view, U937 and HL-60 cells,
which require high concentrations of As2O3 to
undergo apoptosis, become sensitive to low, clinically acceptable
concentrations of As2O3 when cotreated with
these GPx and catalase inhibitors. The induction of apoptosis by
As2O3 involves an early decrease in cellular
mitochondrial membrane potential and increase in
H2O2 content, followed by cytochrome c release, caspase 3 activation, DNA fragmentation, and the classic morphologic changes of apoptosis.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
LOW CONCENTRATIONS (less than or equal to
micromolar concentrations) of As2O3 have been
shown to induce a high rate of clinical remission in patients with
acute promyelocytic leukemia (APL) without severe
toxicity.1-5 Thus, in stark contrast to the carcinogenic
effect of chronic exposure to high doses of arsenic compound,6,7 low concentrations of
As2O3 are of therapeutic value in APL and
perhaps other leukemias.8-11 In vitro studies have shown
that low concentrations of As2O3 induce
apoptosis in APL derived-NB4 cells and primary cultures of APL. In
other leukemic cells, As2O3 can induce
apoptosis but only at higher concentrations that may be unacceptable in
the clinic because of toxicity.8-11
The major feature that distinguishes APL cells from other malignant
hematopoietic cells is the expression of PML-RAR , the product of the
t(15;17) translocation.12-14 PML-RAR is a
transcriptional repressor with dominant negative activity over
RAR.15-17 Studies aimed at understanding the factors
underlying the unique sensitivity of NB4 cells to
As2O3 and, ultimately, how these relate to the expression of PML-RAR form the basis of this report. Our previous work indicated that As2O3-induced apoptosis was
modulated by the cellular glutathione redox system, with increased
intracellular levels of reduced glutathione (GSH) having an inhibitory
effect.11 Because of the antioxidant function of GSH, we
wondered whether 1 µmol/L As2O3 could trigger
NB4 cell apoptosis through the generation of reactive oxygen species
(ROS). We show here that, indeed, the induction of NB4 cell apoptosis
and the refractoriness of other leukemic cells to 1 µmol/L
As2O3 are explained, at least in part, by the
accumulation of higher H2O2 levels in
As2O3-treated NB4 as compared with other
leukemic cells. This difference in intracellular H2O2 concentration is shown to be derived from
a differential pattern of expression of
H2O2-catabolizing enzymes. A causal link between H2O2 levels and apoptosis is supported
by the coordinate regulation of these events in response to both
positive and negative regulation of
H2O2-catabolizing enzymes. Moreover, we show
that, in the presence of glutathione peroxidase (GPx) and catalase
inhibitors, it is possible to achieve high apoptotic rates in leukemic
cells otherwise refractory to a therapeutic concentration of
As2O3 (1 µmol/L). Finally, we demonstrate
that the generation of H2O2 in As2O3-treated NB4 cells triggers apoptosis via
a reduction in mitochondrial membrane potential, cytochrome c release,
and caspase activation.
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MATERIALS AND METHODS |
Reagents.
As2O3 solution (0.1%) was kindly supplied by
Dr Ting-Dong Zhang (Harbin Medical University, Harbin, China).
N-acetylcysteine (NAC), sodium selenite, ethidium bromide, hydrogen
peroxide, and acridine orange were purchased from Sigma Chemical Co (St
Louis, MO) and dissolved in phosphate-buffered saline (PBS). Z-VAD-FMR and GPx assay kit were obtained from Calbiochem (San Diego, CA). Choromethyltetramethylrosamine methyl ester (CMTMR) and
6-carboxy-2',7'-dichlorodihydrofluorescein diacetate
(DCFH-DA; C2938) were obtained from Molecular Probes (Eugene, OR).
Cell lines.
NB4 t(15;17) (obtained from Dr M. Lanotte, Hospital Saint Louis, Paris,
France18), HL-60, U937, K562, and KG1 cells
(from American Type Culture Collection, Rockville, MD) were cultured in
RPMI-1640 medium supplemented with 100 U/mL pencillin, 100 µg/mL
streptomycin, 1 mmol/L L-glutamine, and 10% heat-inactivated fetal
bovine serum. Cells in logarithmic growth were seeded at 1 × 105 cells/mL for studies performed in duplicate and
repeated at least 3 times.
Quantitation of apoptotic cells.
Apoptotic cells were determined by morphology and
fluorescence-activated cell sorting (FACS) analysis with propidium
iodide (PI) as well as TUNEL assay. For morphologic evaluation, cells were stained with acridine orange (AO) and ethidium bromide (EB) and
assessed by fluorescence microscopy as described
previously.19 Briefly, 1 µL of stock solution containing
100 µg/mL AO and 100 µg/mL EB was added to 25 µL of cell
suspension. EB-negative cells with nuclear shrinkage, blebbing, and
apoptotic bodies were counted as apoptotic cells. For FACS analysis
with PI staining, cells were fixed with ice-cold 70% ethanol at a cell
density of 1 × 106/mL and treated with 1 mg/mL RNase
for 30 minutes at 37°C. PI was then added to the solution at a
final concentration of 50 µg/mL and DNA content was quantitated by
flow cytometry.20 TUNEL assay was performed according to
the manufacturer's instructions (PharMingen, San Diego,
CA). Cells were analyzed by fluorescence microscopy and by
flow cytometry using a FACScan. All data were collected, stored, and
analyzed by LYSIS II software (Becton Dickinson, San Jose,
CA). Cells were also analyzed for their DNA content and
cell cycle distribution by flow cytometry analysis of PI-stained nuclei.
Mitochondria membrane potential assay.21
After As2O3 treatment, NB4 cells were washed,
and the medium in each well was supplemented with 50 nmol/L CMTMR and
incubated at 37°C for 15 minutes. The solution was replaced with
dye-free media for a further 10 minutes before washing with PBS. The
cells were cytospun onto slides and were then fixed on ice for 10 minutes with 4% paraformaldehyde. After fixation, the cells were
rinsed with PBS, and the coverslips were mounted onto slides using
Aquamount. Confocal microscopy was then used to resolve individual
mitochondria labeled with CMTMR at the indicated time points. A Leica
TCD confocal scanning microscope coupled to an argon-krypton laser
(Omnichrome, USA) was used. A pinhole of 20 was used with
an excitation filter wavelength of 568 nm and a emission filter of
615/30 nm. Images were scanned using an oil immersion (100×), 1.4 NA objective at 512 × 512 × 8 bits per pixel resolution,
background offset of 0, and averaged 32 times in bidirectional scan
mode. The images were saved in tagged image file format (TIFF) and
transferred to a 100 MHz Pentium PC (Gateway, North Sioux, SD).
Metamorph (Universal Imaging Corp, West Chester, PA) was used to
threshold individual mitochondrial outlines and then to measure the
mean intensity within each mitochondrion.
Enzyme activity assays.
Cells (5 × 107) were washed twice with PBS,
resuspended in PBS, sonicated for 10 seconds, and centrifuged at 14,000 rpm for 10 minutes, and the supernatants were subjected to enzyme
assays. GPx activity was determined using commercial kits (Calbiochem, San Diego, CA). One milliunit of enzyme activity was defined as 1 nmol
NADPH oxidized to NADP per milligram of protein per minute. Catalase
activity was determined by monitoring the rate of decomposition of
H2O2, as assessed by the decrease in absorbance
at 240 nm.22 One unit of activity represented the
consumption of 1 mmol hydrogen peroxide/min/mg protein. The assay
mixture (1 mL) contained 19 mmol/L H2O2 and
defined amounts of cell extract in 50 mmol/L phosphate buffer (pH 7.0)
at 25°C. Glutathione-S-transferase (GST) activity was measured
using 1-chloro-2,4-dinitrobenzene (CDNB) and GSH as
substrates.23 The cell pellets, obtained as described
above, were resuspended in 300 µL of 100 mmol/L potassium phosphate
buffer, pH 6.8, sonicated for 10 seconds at 4°C, and centrifuged at
14,000 rpm for 30 minutes. The assay mixture contained 850 µL of 0.1 mol/L sodium phosphate-1 mmol/L EDTA (pH 6.5), 50 µL of
20 mmol/L GSH, 50 mL of 20 mmol/L CDNB, and 50 µL of clear cell
lysate. The absorbance at 340 nm was continuously recorded for 2 minutes.
H2O2 production.
Production of H2O2 was detected using DCFH-DA,
an uncharged, cell permeant fluorescent probe. Inside the cells,
DCFH-DA is cleaved by nonspecific esterases forming DCFH, which is the
nonfluorescent form and is oxidized to the fluorescent compound
2',7'-dichlorofluorescein (DCF) in the presence of
H2O2.24 Exponentially growing cells (1 × 105 cells/mL) were labeled with 0.5 µmol/L
DCFH-DA for 1 hour and then incubated in the absence or presence of
As2O3 at 37°C for various periods of time.
After washing with PBS, cells (10,000 per point) were analyzed by
FACScan (Becton Dickinson) with excitation and emission settings of 495 and 525 nm, respectively.25 Arithemic histogram statistics analysis was used to determine the mean of the
oxidized DCF peak in each group.
Quantification of DNA fragmentation.
DNA fragmentation was quantified as described previously.20
Cells were harvested by centrifugation, and the pellets were suspended
in lysis buffer containing 15 mmol/L Tris·HCl, 20 mmol/L EDTA, 0.5%
Triton X-100, pH 8.0. After 30 minutes on ice, samples were centrifuged
at 14,000g for 30 minutes, and cellular DNA was extracted.
Electrophoresis was performed in 1% agarose gel in 40 mmol/L
Tris-acetate buffer (pH 7.4) at 50 V. After electrophoresis, DNA was
visualized by ethidium bromide staining.
Western blot analysis.
Protein extracts (50 µg) prepared with RIPA lysis buffer (50 mmol/L
Tris-HCl, 150 mmol/L NaCl, 0.1% sodium dodecyl sulfate [SDS], 1%
NP-40, 0.5% sodium deoxycholate, 1 mmol/L phenylmethyl sulfonyl
fluoride [PMSF], 100 µmol/L leupeptin, and 2 µg/mL aprotinin, pH
8.0) were separated on an 8% or 12% SDS-polyacrylamide gel and
transferred to nitrocellulose membranes. The membranes were stained
with 0.2% Ponceau S red to assure equal protein loading and transfer.
After blocking with 5% nonfat milk, the membranes were incubated with
polyclonal antibody to PARP (Boehringer Mannheim, Indianapolis, IN) and
monoclonal antibodies to Cpp32 and Bcl-2 (Oncogene Research Products,
Cambridge, MA). Immunocomplexes were visualized by chemiluminescence
(ECL kit; Amersham, Arlington Heights, IL).11
| |
RESULTS |
As2O3-induced apoptosis is dependent on
cellular H2O2 levels.
Treatment of NB4 cells with 1 µmol/L As2O3
induced apoptosis, as indicated by morphologic analysis
(Fig 1A), DNA distribution by FACS analysis
demonstrating hypodiploid DNA (Fig 1B), and TUNEL assay (Fig 1C). In
contrast, treatment of U937 cells with even 2 µmol/L
As2O3 did not induce apoptosis (Fig 1A, B, and
C). Although apoptosis was not detected in
As2O3-treated U937 cells, cell growth was
inhibited by As2O3 both in NB4 and U937 cells,
with IC50 of about 0.7 and 1.2 mmol/L at 3 days of
treatment, respectively. The growth inhibition was not correlated with
arrest in a specific cell cycle phase (Fig 1B). These data were
consistent with our previous report that As2O3
inhibited cell growth in several lymphoma cells by prolongation of the
cell cycle without blocking cells in a specific phase.26
Thus, the selective effect of As2O3 in NB4
cells was due to apoptosis induction and not to growth inhibition. This
differential sensitivity to As2O3-induced
apoptosis in NB4 cells was associated with differences in cellular
H2O2 levels that were determined by FACS
analysis of cells labeled with DCFH-DA. The dramatic oxidation of
DCFH-DA to DCF in NB4 cells treated with 50 µmol/L
H2O2 for 1 hour served as a positive control
(Fig 2A). NB4 cells in a standard culture
had a higher oxidized DCF content as compared with U937 cells after
adding DCFH-DA for 1 hour (Fig 2B). The oxidized DCF mean peak
increased from 1.9 to 15.2 within 24 hours of incubation after initial
loading of DCFH-DA in NB4 cells, but only increased from 0.9 to 4.3 in
U937 cells. This is a reflection of a higher
H2O2 content in NB4 cells due to either
increased production or lower catabolism of
H2O2. After treatment with 1 µmol/L
As2O3, the mean of oxidized DCF peak increased compared with the untreated control from 1.9 to 2.4, 4.1 to 6.7, and
15.2 to 21.4 in 1, 8, and 24 hours after initial loading of DCFH-DA,
respectively. In contrast, the mean of oxidized DCF peak was not
increased by 1 µmol/L As2O3 in U937 cells
even after 24 hours of treatment (Fig 2B). Thus, both the constitutive
level of H2O2 and the ability of
As2O3 to increase the level of
H2O2 were correlated with the apoptotic
activity of As2O3.
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| Fig 1.
Comparison of apoptosis induction by
As2O3 in NB4 versus U937 cells. (A)
Fluorescence microscopy determination of apoptotic cells. Cells were
treated with either 0 (control), 1, or 2 µmol/L
As2O3 for up to 4 days, and the number of
apoptotic cells was determined by fluorescence microscopy according to
the morphology. The results are expressed as the percentage of
apoptotic cells in the culture. Values shown are the mean of triplicate
determinations with a standard deviation of less than 10%. (B) FACS
analysis of apoptotic cells. Cells were treated for 3 days with the
indicated concentrations of As2O3 and then
evaluated for DNA content after propidium iodide staining. (C) TUNEL
assay to determine apoptotic cells. Cells were treated with
As2O3 at the indicated time for 3 days.
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| Fig 2.
FACS scan analysis of H2O2
accumulation. (A) NB4 cells were labled with DCFH-DA fluorescent probe
for 1 hour and then treated with or without 50 µmol/L
H2O2 for 1 hour as a positive control. (B) NB4
and U937 cells were treated with 1 µmol/L
As2O3 for the indicated times, with DCFH-DA
fluorescent probe being added 1 hour before the addition of
As2O3. The oxidized DCF was analyzed by FACS.
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The role of H2O2 scavenging enzymes in
As2O3-induced apoptosis.
To determine whether the higher basal levels of
H2O2 in NB4 cells depends on lower
H2O2 catabolism, the major cellular scavenging enzymes GPx and catalase were measured in several leukemia cell lines
with different sensitivities to As2O3-induced
apoptosis. The data in Table 1 show that
the activity of H2O2 scavenging enzymes, GPx
and catalase, was much higher in 4 cell lines that were insensitive to
As2O3-induced apoptosis than in NB4 cells. The
only exception is represented by K562 cells, in which the GPx activity
was lower than that in NB4 cells. However, the very high activity in
these cells of GST, as compared with the low activity in NB4 cells
may compensate for the low activity of GPx and catalase by greater
efflux of cellular As2O3.23,27,28
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Table 1.
The Basal Activities of Antioxidant Enzymes and
As2O3-Induced Apoptosis in Different Human
Leukemia Cell Lines
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Based on the finding that NB4 cells have relatively low
activities of GST, catalase, and GPx (Table 1), we
hypothesized that the higher sensitivity of NB4 cells towards
As2O3-induced apoptosis is related to their low
ability to metabolize the H2O2 produced
during As2O3 treatment. To test this
hypothesis, we tested the effect of selenite, an activator of
GPx.29 To test the effect of a physiologic concentration of
selenite, NB4 cells were grown for several generations in the presence
of 100 nmol/L selenite. This treatment increased GPx activity by a
factor of 7 while having no effect on cell growth. Under these
conditions, As2O3 did not increase
H2O2 levels (Fig
3), and it induced apoptosis in only 7% of the cells, as compared with
58% in cultures not pretreated with selenite
(Table 2). The data also demonstrated that
As2O3 inhibited the activity of GPx and that
this effect was less pronounced in cells pretreated with selenite
(Table 2).
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| Fig 3.
FACS analysis of H2O2
accumulation in NB4 and selenite-pretreated NB4 cells. NB4 cells were
pretreated without (NB4) or with 100 nmol/L sodium selenite for 9 days
(NB4-sele) and then treated with the indicated concentrations of
As2O3 for 24 hours. DCFH-DA was added 1 hour
before the addition of As2O3, and the oxidized
DCF was analyzed by FACS.
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These results strongly suggested that the low
H2O2-metabolizing activity of NB4 cells
predispose them to As2O3-induced apoptosis. As
a further test of this hypothesis, we determined whether the effect of
As2O3 could be enhanced by treatment with
mercaptosuccinic acid (MS),30 an inhibitor of GPx, and
aminotriazol (AT), an inhibitor of catalase. As shown in
Table 3, 100 µmol/L MS had no effect on
cell apoptosis by itself, whereas 20 mmol/L AT moderately increased the
percentage of apoptotic cells in NB4 and HL-60 cells. However, when
combined with 0.5 µmol/L As2O3, which by
itself was ineffective, both inhibitors raised the percentage of
apoptotic NB4 cells to nearly 50%. Remarkably, in HL-60 and U937
cells, which normally respond to only greater than 5 µmol/L
As2O3, cotreatment with 25 or 100 µmol/L MS
and 1 µmol/L As2O3 raised the percentage of
apoptotic cells to 39% and 43%, respectively (Table 3). The combination of 20 mmol/L AT and 1 µmol/L
As2O3 was also more effective than either agent
alone in HL-60 and U937 cells.
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Table 3.
The Effect of GPx Inhibitor and Catalase Inhibitor on
As2O3-Induced Apoptosis in NB4, HL-60, and U937
Cells
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The mechanism of As2O3-induced apoptosis.
Apoptotic mechanisms are drug and cell-type-specific and are
associated with the perturbation of mitochondrial
functions.31 This process results in the activation of
caspase and the fragmentation of DNA, coupled with characteristic
morphologic changes. We tested whether
As2O3-induced apoptosis is preceded by a
decrease of the mitochondrial membrane potential (  M).
We found that, in NB4 cells, M decreased within 4 hours of treatment with 1 µmol/L As2O3 and
decreased further with longer treatment times
(Fig 4). As predicted from the decrease in
M, cytochrome c release into the cytoplasm was
observed; the extent of release was slight 1 day after 1 µmol/L
As2O3 treatment and complete 2 days later
(Fig 5). Concomitant with the
As2O3 induction of maximal cytochrome c
release, Cpp32 was activated, as shown by the degradation of its
precursor (32 kD) and the cleavage of PARP, a Cpp32 substrate. These
events were independent of Bcl-2 degradation
(Fig 6A) and were followed by
DNA fragmentation (Fig 6B). As expected, high concentrations (200 µmol/L) of the general caspase inhibitor, Z-VAD-FMK, inhibited
As2O3-induced apoptosis.
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| Fig 4.
Decrease in mitochondrial membrane potential
( M) in NB4 cells treated with
As2O3. The M of individual
mitochondria was detected using confocal microscopy imaging of CMTMR
fluorescence. NB4 cells were treated with 1 µmol/L
As2O3 for the indicated times.
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| Fig 5.
As2O3 treatment induces
cytochrome c release from mitochondria. NB4 cells were treated with 1 µmol/L As2O3 for the indicated times and the
cytochrome c content of mitochondrial and cytosolic fractions was
detected by Western blot analysis as described.49
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| Fig 6.
As2O3 treatment induces
caspase-3 activation but not Bcl-2 degradation. (A) Activation of CPP32
and lack of Bcl-2 modulation after 3 days of treatment with the
indicated doses of As2O3. (B) Effect of the
same As2O3 treatment on DNA fragmentation. (C)
Caspase inhibitor Z-VAD-FMK blocked
As2O3-induced apoptosis. NB4 cells were treated
for 3 days with 1 µmol/L As2O3 or 200 µmol/L Z-VAD-FMK alone or in combination; Z-VAD-FMK was added 4 hours
before the addition of As2O3.
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DISCUSSION |
Recent developments suggest that a number of diverse apoptotic stimuli
share a mechanistic pathway characterized by the generation of ROS and
the loss of mitochondrial membrane potential, with subsequent outer
mitochondrial membrane permeability changes, release of cytochrome c,
and caspase activation.31-34 Thus, agents as diverse as
ceramide, tumor necrosis factor-, UV irradiation, and anthracyclines
have been shown to trigger apoptosis via ROS production.24,35-38 Our findings indicate that
As2O3 represents a novel apoptotic stimulus
functioning via ROS, specifically H2O2, generation. This conclusion is supported by the following key observations. (1) Treatment of NB4 cells with an apoptotic
concentration of As2O3 (1 µmol/L) inhibits
the activity of GPx, an H2O2-catabolizing enzyme (Table 2). (2) The same treatment results in elevated intracellular H2O2 levels (Fig 2). (3)
Pretreatment with selenite, a GPx activator, results in high GPx
activity, lack of H2O2 accumulation, and
inhibition of apoptosis (Table 2 and Fig 3). (4) Cotreatment with MS, a
GPx inhibitor, and, to a lesser extent, with AT, a catalase inhibitor,
potentiates the induction of apoptosis by As2O3
(Table 3).
The high sensitivity of NB4 APL cells to As2O3
appears to reside in a leukemic cell-specific pattern of expression of
GPx and catalase,39 as well as GST, which represents the
major As2O3 detoxifying enzyme.40
Thus, NB4 cells have low GST, GPx, and catalase activities relative
to 4 other non-APL leukemic cell lines (Table 1), suggesting that NB4
cells detoxify As2O3 and catabolize
H2O2 less efficiently.
These findings are consistent with our previous work showing that
As2O3-induced apoptosis is blocked by NAC and
lipoic acid, agents that increase GSH, and is enhanced by BSO, a
GSH-depleting agent.11 Thus, high levels of GSH, which is a
proton donor for the GPx-catalyzed breakdown of
H2O2 and for the GST-catalyzed detoxification of As2O3, ensure rapid rates for
these reactions, thus conferring a protective effect. Our findings are
also consistent with the observations that 40 µmol/L arsenite induces
apoptosis in hamster CHO41 and NIH3T3 cells42
with generation of ROS, that H2O2-resistant CHO
cells are less responsive,43 and that catalase-deficient
CHO cells are hypersensitive to arsenic.44 The ascorbic
acid synergism of As2O3-induced apoptosis in
NB4 is mediated by H2O2 production, because it
is inhibited by catalase.11
We suspect that As2O3 acts to increase
H2O2 levels in NB4 cells mainly by inhibiting
the activity of GPx, which is a major H2O2
scavenging thiol-enzyme. We speculate that
As2O3 inhibition of GPx is mediated by the
binding of arsenic to vicinal thiol group in GPx,30 but
this remains to be tested. The low levels of GST limit
detoxification of cellular As2O3, providing
higher As2O3 binding ability that contributes
to direct inactivation of GPx. On the other hand, it is possible that
As2O3 also increases the mitochondrial
production of H2O2. For instance, 20 µmol/L arsenite leads to H2O2 accumulation through a
mechanism thought to depend on the activation of NADPH
oxidase.42 It should also be pointed out that peroxidases
other than GPx may also be targeted by As2O3.
An example is thioredoxin peroxidase, another thiol peroxidase that
protects against mitochondrial permeability transition by removing
H2O2.45
We have demonstrated that apoptosis in
As2O3-treated NB4 cells proceeds via the
classical pathway described for other ROS inductive
signals.46-49 Thus, As2O3 elicited
a rapid decrease in mitochondrial membrane potential (Fig 4), which
preceded the release of cytochrome c, Cpp32 activation, DNA
fragmentation, and morphologic evidence of apoptosis (Fig 5 and 6).
However, in contrast to previous reports,8 we did not
observe Bcl-2 degradation in NB4 cells treated with 1 to 2 µmol/L
As2O3. This is consistent with a recent report
showing that Bcl-2 is not degraded in NB4 cells, even when treated with
8 µmol/L As2O3.50 Moreover, human
t(14;18) B-cell lymphoma su-DHL-4 cells overexpressing
Bcl-2 are sensitive to 2 µmol/L As2O3 without
degradation of Bcl-2.11 On the other hand,
NIH3T342 and HL-60 cells with forced expression of Bcl-2 are more resistant to As2O3-induced apoptosis
(Jing et al, unpublished data), consistent with the
finding that cells overexpressing Bcl-2 are resistant to
H2O2-induced cell death.25
As2O3-induced apoptosis in NB4 cells is blocked
by the caspase inhibitor Z-VAD-FMK (Fig 6). This result is consistent
with the previous observation that Z-VAD-FMK blocked
As2O3-induced apoptosis in lymphoma
cells.51 Our current view of the apoptotic pathway induced
by As2O3, as supported by the above-noted data,
is depicted diagrammatically in Fig 7.
A fundamental question is why are NB4 APL cells uniquely sensitive to
As2O3? In other words, how does the PML-RAR
fusion protein that represents the molecular signature of APL confer sensitivity to As2O3? As already discussed, our
data point to the low GST, GPx, and catalase activities of NB4 cells
as a logical explanation for their sensitivity to
As2O3. What then is the relationship between
PML-RAR and the activity of these enzymes? We suspect that the
answer lies partly in the facts that GST is an RA-inducible gene52 and that PML-RAR is a dominant repressor of
RAR function.15-17 Thus, it seems likely that PML-RAR
inhibits the RAR activation of GST in NB4 cells, leading to
reduced enzyme expression and activity. RA has also been shown to
upregulate GPx and catalase expression in some cell types, but whether
this is a transcriptional effect remains to be
demonstrated.53 Thus, it is conceivable that PML-RAR
also interferes with GPx and catalase expression. These are testable
hypotheses that we are currently pursuing. For instance, one prediction
is that, if PML-RAR protein expression is decreased by pretreatment
with RA,54 then NB4 cells may be less sensitive to
As2O3-induced apoptosis. Our preliminary
experiments suggest that this is in fact the case (Jing et al,
unpublished data). In addition, cotreatment of NB4 cells
with tRA and As2O3 has been shown to result in
decreased apoptosis.10 Whatever the mechanism through which
PML-RAR confers sensitivity to As2O3, it is
clear that PML-RAR is indeed required for the therapeutic effect of
As2O3; this is true both in vitro, as shown by
the sensitization of U937 cells to As2O3 by
ectopic PML-RAR expression,55 and in vivo, as shown by
the finding that only 2 of 53 APL patients that did not experience
clinical remission during As2O3 therapy had
PML-RAR-negative disease.56
Interestingly, we have found that P388 lymphoma cells are growth
inhibited by As2O3 with an IC50 of
1.7 µmol/L, and that P388/adr cells with multidrug resistance (MDR1)
to adriamycin (482-fold) and taxol (111-fold)57 remain
responsive to As2O3 (IC50 of 2.0 µmol/L). This suggests that As2O3 is not a
substrate for the MDR1 drug efflux pathway, which is consistent with
other reports40.58 and our proposal that GST-mediated
efflux represents the major As2O3 efflux
pathway in NB4 cells. Furthermore, the lack of cross-resistance between
adriamycin and As2O3 is consistent with the
clinical observation that anthracycline-resistant APL is responsive to
As2O3 therapy.2,4,5
It has been recently reported that the clinical remission induced by
As2O3 in APL patients and in transgenic mice is
accompanied in part by the induction of cell
differentiation.5,59 It remains to be seen to what extent
the H2O2-dependent pathway we have unmasked here contributes to the induction and/or maintenance of clinical remission. It will also be of interest to pursue the feasibility of
extending As2O3 therapy to other leukemias or
lymphomas that have shown variable sensitivity to
As2O351,60 by appropriate cotreatment with drugs capable of altering the ROS balance in favor of
cell death activation, as exemplified by our in vitro findings of
apoptosis induction in HL-60 and U937 cells by
As2O3 and MS.
| |
ACKNOWLEDGMENT |
The authors appreciate the advice of Dr George Acs throughout these
studies and critical reading by Dr Rafael Mira-y-Lopez.
| |
FOOTNOTES |
Submitted December 22, 1998; accepted May 21, 1999.
Supported by National Institutes of Health Grant No. 5RO1CA59936-03-05,
the Gloria and Sidney Danziger Foundation, and the Samuel Waxman Cancer
Research Foundation.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Yongkui Jing, PhD, Division of Neoplastic
Diseases, Department of Medicine, Box 1178, Mount Sinai Medical Center,
One Gustave L. Levy Place, New York, NY 10029-6547.
| |
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Targeted Degradation of the AML1/MDS1/EVI1 Oncoprotein by Arsenic Trioxide
Cancer Res.,
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Buthionine Sulfoximine Enhancement of Arsenic Trioxide-Induced Apoptosis in Leukemia and Lymphoma Cells Is Mediated via Activation of c-Jun NH2-Terminal Kinase and Up-regulation of Death Receptors
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P. Kannan-Thulasiraman, E. Katsoulidis, M. S. Tallman, J. S. C. Arthur, and L. C. Platanias
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N. Giafis, E. Katsoulidis, A. Sassano, M. S. Tallman, L. S. Higgins, A. R. Nebreda, R. J. Davis, and L. C. Platanias
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J. Alexandre, C. Nicco, C. Chereau, A. Laurent, B. Weill, F. Goldwasser, and F. Batteux
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A. Lemarie, C. Morzadec, D. Merino, O. Micheau, O. Fardel, and L. Vernhet
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A. M. Ramos, C. Fernandez, D. Amran, P. Sancho, E. de Blas, and P. Aller
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D. Douer and M. S. Tallman
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L. Xia, D. Chen, R. Han, Q. Fang, S. Waxman, and Y. Jing
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Y. Qian, K. J. Liu, Y. Chen, D. C. Flynn, V. Castranova, and X. Shi
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L. Zhou, Y. Jing, M. Styblo, Z. Chen, and S. Waxman
Glutathione-S-transferase {pi} inhibits As2O3-induced apoptosis in lymphoma cells: involvement of hydrogen peroxide catabolism
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Z. Diaz, M. Colombo, K. K. Mann, H. Su, K. N. Smith, D. S. Bohle, H. M. Schipper, and W. H. Miller Jr
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A. M. Evens, P. Lecane, D. Magda, S. Prachand, S. Singhal, J. Nelson, R. A. Miller, R. B. Gartenhaus, and L. I. Gordon
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Arsenic Trioxide-Induced Death of Neuroblastoma Cells Involves Activation of Bax and Does Not Require p53
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K. Davison, K. K. Mann, S. Waxman, and W. H. Miller Jr
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K. Ito, T. Nakazato, A. Murakami, K. Yamato, Y. Miyakawa, T. Yamada, N. Hozumi, H. Ohigashi, Y. Ikeda, and M. Kizaki
Induction of Apoptosis in Human Myeloid Leukemic Cells by 1'-Acetoxychavicol Acetate through a Mitochondrial- and Fas-Mediated Dual Mechanism
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C. Fernandez, A. M. Ramos, P. Sancho, D. Amran, E. de Blas, and P. Aller
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Melanoma Differentiation Associated Gene-7, mda-7/Interleukin-24, Induces Apoptosis in Prostate Cancer Cells by Promoting Mitochondrial Dysfunction and Inducing Reactive Oxygen Species
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W. H. Miller Jr., H. M. Schipper, J. S. Lee, J. Singer, and S. Waxman
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G. J. Roboz, S. Dias, G. Lam, W. J. Lane, S. L. Soignet, R. P. Warrell Jr, and S. Rafii
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Y. Huang, C. M. Horvath, and S. Waxman
Regrowth of 5-Fluorouracil-treated Human Colon Cancer Cells Is Prevented by the Combination of Interferon {{gamma}}, Indomethacin, and Phenylbutyrate
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S. Zhuang, J. T. Demirs, and I. E. Kochevar
p38 Mitogen-activated Protein Kinase Mediates Bid Cleavage, Mitochondrial Dysfunction, and Caspase-3 Activation during Apoptosis Induced by Singlet Oxygen but Not by Hydrogen Peroxide
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B. A. Wagner, G. R. Buettner, L. W. Oberley, C. J. Darby, and C. P. Burns
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Y. Yang, J.-Z. Cheng, S. S. Singhal, M. Saini, U. Pandya, S. Awasthi, and Y. C. Awasthi
Role of Glutathione S-Transferases in Protection against Lipid Peroxidation. OVEREXPRESSION OF hGSTA2-2 IN K562 CELLS PROTECTS AGAINST HYDROGEN PEROXIDE-INDUCED APOPTOSIS AND INHIBITS JNK AND CASPASE 3 ACTIVATION
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M. Neuss, R. Monticone, M. S. Lundberg, A. T. Chesley, E. Fleck, and M. T. Crow
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TOP
ABSTRACT
INTRODUCTION