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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 1 (January 1), 1999:
pp. 268-277
Malignant Cells Can Be Sensitized to Undergo Growth Inhibition and
Apoptosis by Arsenic Trioxide Through Modulation of the Glutathione
Redox System
By
Jie Dai,
Rona S. Weinberg,
Samuel Waxman, and
Yongkui Jing
From the Rochelle Belfer Chemotherapy Foundation Laboratory, the
Division of Neoplastic Diseases, the Division of Hematology, the
Department of Medicine, Mount Sinai Medical Center, New York, NY.
 |
ABSTRACT |
Arsenic trioxide (As2O3) induces clinical
remission in acute promyelocytic leukemia (APL) with minimal toxicity
and apoptosis in APL-derived NB4 cells at low (1 to 2 µmol/L)
concentration. We examined the basis for NB4 cell sensitivity to
As2O3 to identify experimental conditions that
would render other malignant cells responsive to low concentrations of
As2O3. The intracellular glutathione (GSH)
content had a decisive effect on As2O3-induced
apoptosis. Highly sensitive NB4 cells had the lowest GSH and the
sensitivity of other cell lines was inversely proportional to their GSH
content. The t(14;18) B-cell lymphoma cell line had low GSH levels and sensitivity to As2O3 at levels slightly higher
than in APL cells. Experimental upmodulation of GSH content decreased
the sensitivity to As2O3. Ascorbic acid and
buthionine sulfoxide (BSO) decreased GSH to a greater extent, and
rendered malignant cells more sensitive to
As2O3. As2O3-induced
apoptosis was not enhanced by ascorbic acid in normal cells, suggesting
that the combination of ascorbic acid and As2O3
may be selectively toxic to some malignant cells. Ascorbic acid
enhanced the antilymphoma effect of As2O3 in
vivo without additional toxicity. Thus, As2O3
alone or administered with ascorbic acid may provide a novel therapy
for lymphoma.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
ARSENIC TRIOXIDE
(AS2O3), in a protocol originally developed
in Harbin, China, has recently been confirmed to be an effective
treatment for acute promyelocytic leukemia (APL) in patients who
relapsed after chemotherapy and all-trans retinoic acid (tRA)
treatment.1-4 The peak As2O3 plasma
concentration in patients was 5 to 7 µmol/L and rapidly diminished to
a more sustained level of 1 to 2 µmol/L, which is thought to be the
therapeutic range in treating APL.3
As2O3 (1 to 2 µmol/L) induces apoptosis in
the t(15;17) APL cell line NB4 and APL cells in vitro and, to some
extent, in vivo in patients without significant
myelosuppression.5,6 As2O3-induced
apoptosis in NB4 cells was associated with rapid degradation of
PML/RAR- protein,6 the oncogenic protein that is the
product of the t(15;17) translocation characteristic of APL.7,8 The fact that, among a series of 37 patients, the two APL patients who failed to respond to As2O3
lacked measurable PML/RAR- message by polymerase chain reaction
(PCR) suggests an important role for PML/RAR- protein in
As2O3-induced apoptosis. Additional clinical
experience obtained in Harbin, China by Ting Dong Zhang
(personal communication, 1996) showed As2O3 to
be effective in patients with conventional chemotherapy-resistant
lymphoproliferative and myeloproliferative disorders. Because
As2O3 is reported to be clinically effective in
patients previously treated with alkylating agents and
anthracyclines,3,4 there should be lack of cross resistance
between As2O3 and these chemotherapeutic
agents.
Organic arsenic compounds are significantly more toxic than inorganic
arsenic because of high binding affinity to vicinal SH group-containing
proteins.9 Organic arsenicals such as melasporal, although
more potent than As2O3 in inducing apoptosis in
NB4 cells, are clinically too toxic to be used in the treatment of
APL.10 Most previous studies that investigated the cellular
and biochemical effects of arsenic were performed using concentrations
greater than 5 µmol/L, often 50 µmol/L, and the relevance to
therapeutic levels (1 to 2 µmol/L) remains to be determined. These
high concentrations may initiate gene transcription by altering the
phosphorylation state of signal transduction proteins such as tyrosine
kinases.11 Arsenic effects phosphorylation by activating
specific kinases, by inhibiting thiol-dependent phosphatases, or by
interfering with phosphotransferase reactions.12 The
protective effects of thiols, such as glutathione,
cysteine,13 and dithiols, such as dithiotreitol, against
the toxic effects of arsenic suggests that arsenic toxicity results
from forming reversible bonds with the thiol groups of regulatory
proteins.
The glutathione (GSH) redox system is known to modulate the
growth-inhibitory effect of arsenicals.14-18 Until
recently, the effect of this intracellular defense system has not been
studied in arsenic-induced apoptosis. As5+, cadmium,
thalium, selenium, zinc, or mercury did not induce apoptosis at 1 µmol/L in NB4 cells, suggesting a unique effect of As3+
(as in As2O3) in this process.19
The findings that arsenites (40 µmol/L) can induce apoptosis in
hamster CHO cells,20 that hydrogen peroxide-resistant CHO
cells are less responsive,21 and that catalase-deficient
CHO cells are hypersensitive suggests an important role for hydrogen
peroxide as a mediator of arsenic-induced apoptosis.21
There is a need to understand better the cellular response to
As2O3 at 1 to 2 µmol/L concentrations because
it appears to be cancer-selective and therapeutically achievable.
Accordingly, we investigated whether the GSH content and its modulation
can be correlated with the sensitivity of As2O3
in NB4 and other malignant cells. We found that the sensitivity to
As2O3-induced apoptosis was inversely related
to the intracellular GSH content and that pharmacologic modulation of
intracellular GSH content modulates sensitivity to
As2O3.
| |
MATERIALS AND METHODS |
Reagents.
A 0.1% As2O3 solution was kindly supplied by
Dr Ting Dong Zhang (Harbin, China). Buthionine sulfoxide (BSO),
N-acetylcysteine (NAC), ascorbic acid, catalase, and lipoic
acid were purchased from Sigma Chemical (St Louis, MO). All of the
agents were dissolved in phosphate-buffered saline (PBS), except lipoic
acid, which was dissolved in 100% ethanol at a stock solution of 0.1 mol/L. The final ethanol concentration in the medium was not greater than 0.1%.
Cell lines.
NB4 t(15;17) (obtained from Dr M. Lanotte),22 HL-60 cells
(American Type Culture Collection [ATCC], Rockville,
MD), and t(14;18) B-cell lymphoma su-DHL-4 cell lines,
which overexpress Bcl-2 (obtained from Dr M. Cleary),23
were cultured in RPMI-1640 medium, supplemented with 100 U/mL
penicillin, 100 µg/mL streptomycin, 1 mmol/L L-glutamine, and 10%
fetal bovine serum. Human breast cancer cell lines T47D and MDA-MB-468
were obtained from ATCC and cultured as previously
reported.24 RM5.21 human fibroblasts from normal breast
tissue were isolated from reduction mammaplasty specimen and human
embryo fibroblasts (HEF) were cultured as described.24 Cell
viability was determined by trypan-blue exclusion. The cells were in
logarithmic growth when seeded at 1 × 105 cells/mL for
studies performed in duplicate and repeated at least three times.
Quantitation of apoptotic cells.
Apoptotic cells stained with acridine orange (AO) and ethidium bromide
(EB) were assessed by fluorescence microscopy. Briefly, 1 µL of stock
solution containing 100 µg/mL AO and 100 µg/mL EB was added to 25 µL of cell suspension. Total cells, as well as apoptotic cells that
showed nuclear shrinkage, blebing, and apoptotic bodies, were counted.
DNA fragmentation analysis was performed as described
previously.25
Measurement of intracellular GSH.
Intracellular GSH contents were measured using Glutathione Assay Kit
(Calbiochem, San Diego, CA). In brief, 5 × 106 cells were
homogenized in 5% metaphosphoric acid using a Teflon pestle (Racine, WI). Particulate matter was separated by centrifugation at 4,000g. Supernatant was used for GSH measurement according to the manufacturer's instruction, while the pellet was dissolved in 1 mol/L NaOH and analyzed for protein by Bio-Rad protein assay (Bio-Rad
Laboratories, Hercules, CA). The GSH content was expressed as nanomoles
per milligram protein.
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 phenylmethylsulfonyl fluoride [PMSF], 100 µmol/L leupeptin, and 2 µg/mL aprotinin, pH
8.0) were separated through an 8% or 12% SDS-polyacrylamide gel and
transferred to nitrocellulose membranes. The membranes were stained
with 0.2% Ponceau red to assure equal protein loading and transfer.
After blocking with 10% nonfat milk, the membrane was incubated with
polyclonal antibody to PARP (Boehringer Mannheim, Indianapolis, IN),
and monoclonal antibodies to Cpp32 and Bcl-2 (Oncogene Research
Products, Cambridge, MA). The immunocomplex was visualized by
chemoluminescence (ECL kit; Amersham, Buckinghamshire, UK).
Colony-forming assays of human bone marrow and peripheral blood
cells.
Mononuclear cells (MNC) from blood and/or bone marrow from
normal adults collected into syringes containing 50 U heparin were prepared following dilution 1:1 with medium, layered onto an equal
volume of Ficoll-Paque, and centrifuged at 450g for 30 minutes at 18°C. For methylcellulose cultures, MNC were cultured according to
methods previously described.26 Each milliliter of culture contained 300,000 MNC, 0.8% methylcellulose in alpha medium, 30% fetal bovine serum, 1% bovine serum albumin (BSA; COHN fraction IV),
0.1 mmol/L 2-mercaptoethanol, 0.1 U penicillin, and 0.1 µg/mL streptomycin. Erythroid cultures contained erythropoietin (2 U/mL). Myeloid cultures contained granulocyte-macrophage colony-stimulating factor (GM-CSF; 2 ng/mL) and interleukin-3 (IL-3; 50 U/mL). Cultures were performed in triplicate in 0.3-mL vol in Nunc
four-well dishes (Intermed, Roskilde, Denmark) and incubated at 37°C
in 4% CO2 with or without As2O3,
ascorbic acid, or the combination. Colonies derived from colony-forming
units erythrocyte (CFU-E) were counted on day 7 and those from
burst-forming unitserythrocyte (BFU-E) and CFU-GM on day 13 using a
Stereozoom dissecting microscope (Bausch & Lomb,
Rochester, NY).
3H-thymidine incorporation in
phytohemagglutinin-activated lymphocytes.
Lymphocytes were isolated from normal adult blood and
3H-thymidine incorporation was measured in
phytohemagglutinin (PHA)-activated lymphocytes according to the
reported method.27
In vivo experiments.
BDF1 female mice were obtained from Charles River Laboratories
(Wilmington, MA). All procedures confirmed to the National Institutes of Health (NIH) guidelines for the care and use of laboratory animals. Transplantable P388D1 cells were obtained from ATCC
and carried intraperitoneally in BDF1 mice. For
experiments, 0.1 mL containing 2 × 106 cells obtained
from ascites after 7 days of transplantation were inoculated
intraperitoneally. Mice were randomly divided into four groups each
with five mice. After 24 hours, each group was given saline,
As2O3 (5 mg/kg), and ascorbic acid (500 mg/kg)
alone or in combination intraperitoneally every other day for seven times. The percentage increase in lifespan over control (ILS) was
calculated as follows: ILS% = T/C% minus 100, where T is the test
mean survival time, and C is the control mean survival time. Paired
t-test was used to determine significance.
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RESULTS |
The growth inhibitory and apoptotic effect of
As2O3 inversely correlates with GSH content of
NB4, su-DHL-4, and HL-60 cells.
The 50% inhibitory concentration (IC50) after 3 days of
As2O3 treatment for NB4 cells was 0.5 µmol/L,
for su-DHL-4 cells 1.5 µmol/L, and for HL-60 cells greater than 3 µmol/L (Fig 1A).
As2O3 1.2 µmol/L induced apoptosis at day 3 in 50% of the NB4 cells, whereas 1.8 µmol/L was required in su-DHL-4
cells (Fig 1B), while even 5 µmol/L As2O3 was
insufficient to induce 50% apoptosis in HL-60 cells. The GSH content
was three times greater in HL-60 cells than in NB4 cells, whereas in
su-DHL-4 cells GSH content fell in between these two values (Fig 1C).
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| Fig 1.
Growth inhibition (A) and apoptosis (B) induced
by As2O3 in NB4, su-DHL-4, and HL-60 cells, and
basal GSH levels (C). Cells were treated with different concentrations
of As2O3 for 3 days. Cell growth and apoptotic
cell number were determined with fluorescence staining as described in
Materials and Methods. Values are the mean of three independent
experiments.
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Cell growth inhibition and apoptotic effect of
As2O3 is modulated by experimentally changing
the GSH content.
Increasing the GSH content by NAC treatment28 in NB4 cells
(Table 1) prevented 2 µmol/L
As2O3 induction of apoptosis (Fig 2A). Similarly, lipoic acid completely
blocked As2O3-induced apoptosis, perhaps by
binding As2O3 to its vicinal thiol groups and
increasing GSH content.29 Both NAC and lipoic acid
treatment inhibited As2O3-induced activation of
CPP32 and apoptosis. However, NAC did not and lipoic acid only
partially inhibited the degradation of PML/RAR- protein (Fig 2B,
lanes 4 and 6). Thus, the degradation of PML/RAR- alone was not
sufficient for the As2O3 induction of apoptosis
(Fig 2B). In contrast, BSO is known to decrease intracellular GSH
levels by inhibition of  -glutamylcysteine synthase
activity.30 During a 24-hour treatment, BSO alone reduced
the GSH level to approximately 10 nmol/mg protein in all three cell
lines (Table 1), while it did not affect cell growth or apoptosis (Fig
3). Treatment with BSO for 4 hours followed by 1 µmol/L
As2O3 for 12 hours sensitized the three cell
lines to As2O3 since 75% of the NB4 cells,
70% of the su-DHL-4 cells, and 55% of the HL-60 cells underwent
apoptosis (Fig 3). Thus, leukemic cell
lines devoid of PML/RAR- can be made as sensitive to
As2O3 as NB4 cells.
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| Fig 2.
(A) NAC and lipoic acid (LA) blocked
As2O3-induced apoptosis but not PML/RAR-
degradation in NB4 cells. NB4 cells were treated with 2 µmol/L
As2O3 alone or together with 10 mmol/L NAC or
100 µmol/L LA for 24 and 72 hours. Apoptotic cells were determined by
fluorescence staining as described in Materials and Methods. Values are
the mean of three independent experiments. (B) NAC and LA blocked
As2O3-induced activation of Cpp32 and cleavage
of PARP, but not PML/RAR- degradation in NB4 cells. Lane 1, control;
lane 2, As2O3; lane 3, LA; lane 4, As2O3 + LA; lane 5, NAC; lane 6, As2O3 + NAC. Cells were treated with
concentrations described above for 24 hours.
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| Fig 3.
BSO enhanced As2O3-induced
apoptosis in NB4, su-DHL-4, and HL-60 cells. Cells were pretreated with
BSO 100 µmol/L for 4 hours, then with or without
As2O3 1 µmol/L for 12 hours. Values are the
mean of three independent experiments.
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In HL-60 and su-DHL-4 cells, ascorbic acid acts as an oxidizing agent
decreasing the GSH content of the cells and synergizing with the
growth-inhibitory and apoptotic effect of As2O3
(Fig 4 and Table 1). The apoptotic
morphology and DNA ladder, as well as Cpp32 activation, in su-DHL-4
cells treated with 1 µmol/L As2O3 and 62.5 µmol/L ascorbic acid are shown in Fig 5.
In contrast to ascorbic acid, dehydroascorbic acid did not potentiate
the effect of As2O3 (Table
2). It is plausible that the autooxidation of ascorbic acid that results in the formation of
H2O231 is responsible for the
synergistic effect obtained by ascorbic acid. This suggestion is
substantiated by our findings that (1) H2O2 synergized the effect of As2O3 (Table 2), and
(2) catalase abolished the synergistic effects obtained by ascorbic
acid.
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| Fig 4.
Ascorbic acid (AA) enhanced
As2O3-induced apoptosis in su-DHL-4 (A,B) and
HL-60 cells (C,D). Cells were treated with 1 µmol/L
As2O3, 62.5 µmol/L AA alone or together. Cell
viability and apoptotis were determined as described in Materials and
Methods. Values are the mean of three independent experiments.
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| Fig 5.
As2O3 combined with AA induces
apoptosis in su-DHL-4 cells. (A) Morphologic features of apoptosis.
Cells were treated for 24 hours. 1, Without treatment; 2, As2O3 (1 µmol/L); 3, AA (62.5 µmol/L); 4, As2O3 (1 µmol/L) with AA (62.5 µmol/L).
Apoptotic cells were determined with fluorescence staining as described
in Materials and Methods. (B) DNA fragmentation. Cells were treated for
24 hours and total DNA was isolated and separated on agarose gel. DNA
ladder was visualized with EB as described in Materials and Methods.
Lane M, size markers,  DNA HindIII digest and  x174 RF DNA
HaeII digest; lane 1, control; lane 2, As2O3 (1 µmol/L); lane 3, AA (62.5 µmol/L);
lane 4, As2O3 (1 µmol/L) + AA (62.5 µmol/L); lane 5, AA (125 µmol/L); lane 6, As2O3 (1 µmol/L) + AA (125 µmol/L). (C)
Activation of CPP32 and effect on Bcl-2 by treatments as in B.
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The synergistic growth-inhibitory effect of
As2O3 and ascorbic acid was observed not only
in cell lines, but also in primary cultures of chronic lymphocytic
leukemia (CLL) cells (Table 3). The data in
Table 3 show that a 5-day exposure of the cells to 1 µmol/L
As2O3 or 125 µmol/L ascorbic acid alone had
minimal effect on cell growth, but the combination of the two agents
reduced the viable cell number by approximately 60% (Table
3).
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Table 3.
Effect of Combined Treatment of
As2O3 and Ascorbic Acid of Primary Cultures
of Chronic Lymphocytic Leukemia Cells
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As2O3 (1 µmol/L) inhibited cell viability in
two human breast cancer cells (Table 4).
MDA-MB-468, a breast cancer cell line with low
glutathione-S-transferase (GST) activity, was remarkably sensitive to 1 µmol/L As2O3 (97% inhibition of growth),
while T47D with higher GST activity was less sensitive to
As2O3 (Table 4). The sensitivity to
As2O3 was inversely proportional to GSH levels
in both breast carcinoma cell lines. Ascorbic acid increased T47D
sensitivity to As2O3. In contrast, normal human
breast fibroblasts or HEF were more resistant to
As2O3 alone or in combination with ascorbic
acid.
Effect of As2O3 and ascorbic acid on normal
hematopoietic cells.
Human bone marrow or peripheral blood MNC grown in methylcellulose were
treated with As2O3 and ascorbic acid alone or
in combination for up to 2 weeks. A 1 µmol/L quantity of
As2O3 inhibited CFU-E cells by approximately
60%, but had minimal effect on CFU-GM or BFU-E colony formation.
As2O3 significantly inhibited colony-forming ability at concentrations greater than 2 µmol/L (Fig
6A). Treatment with ascorbic acid did not
inhibit colony formation at concentrations less than 500 µmol/L (Fig
6B). Ascorbic acid did not enhance As2O3 inhibition of CFU-GM or BFU-E, but at high concentration (500 µmol/L)
enhanced As2O3 inhibition of CFU-E (Fig 6C).
Similarly, the mitogenic response to PHA by normal lymphocytes as
measured by 3H-thymidine incorporation was not
significantly affected by As2O3 and the effect
was not augmented by cotreatment with up to 125 µmol/L ascorbic acid
(Fig 7). Thus, it seems that malignant
cells are more sensitive to the combined treatment of ascorbic acid and
As2O3 than normal cells.
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| Fig 6.
Effect of As2O3 and AA on
colony-forming ability of human bone marrow or peripheral blood
progenitor cells. (A) As2O3, (B) AA alone, or
(C) together at the indicated concentrations. Colony-forming ability
was determined as described in Materials and Methods. Results are
representative of three independent experiments each performed in
triplicate.
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| Fig 7.
Effect of As2O3 and AA on
3H-thymidine incorporation of PHA activated lymphocytes.
Lymphocytes in primary culture were treated with indicated drugs for 3 days.
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Ascorbic acid enhances As2O3 antilymphoma
effect in vivo.
In vivo studies to evaluate the effect of ascorbic acid and
As2O3 in the treatment of lymphoma were
initiated. Mouse lymphoma P388D1 cells, which demonstrate
in vitro ascorbic acid enhancement of As2O3
growth inhibition, were implanted (2 × 106 cells) into
the peritoneum of BDF1 mice. On the second day
As2O3 (5 mg/kg) and ascorbic acid (500 mg/kg)
alone or in combination was given every other day for seven times. The
combination treatment improved survival time, with an ILS of 40%,
whereas single-agent treatment at these nontoxic concentrations did not
influence survival (Table 5). The
significantly prolonged survival was without additive toxicity as
compared with As2O3 or ascorbic acid treatment
alone.
| |
DISCUSSION |
The therapeutic efficacy of As2O3 in
APL2-4 prompted our investigations to elucidate the
mechanism of action of As2O3 in APL derived NB4
cells. Our data indicate that the modulation of the redox system, and
particularly the GSH content, determines the sensitivity of the cells
toward As2O3. We found that 1 to 2 µmol/L
As2O3, the therapeutically effective
concentrations of As2O3 which induce remission
in APL with minimal toxicity,3 induces apoptosis within 3 days in NB4 cells while other leukemic cells are less sensitive to
As2O3 (Fig 1). The effect of
As2O3 is associated with the morphologic
changes characteristic of apoptosis, with activation of CPP32, cleavage
of PARP, and fragmentation of DNA (Figs 2 and 5). However, degradation
of Bcl-2 previously reported during
As2O3-induced apoptosis of NB4
cells5 was not observed in su-DHL-4 cells even in the
presence of ascorbic acid (Fig 5C) and may be cell-type specific.
We investigated whether PML/RAR-, the oncogenic protein of APL, is
responsible for the exquisite sensitivity of NB4 toward As2O3. We have confirmed6 that
As2O3 at concentrations less than 0.5 µmol/L
for 3 days of treatment induces degradation of PML/RAR- in NB4 cells
without inducing apoptosis. In the presence of NAC or lipoic acid,
As2O3, even at high concentration, does not
induce apoptosis, but it is still effective in inducing degradation of
the PML/RAR- protein (Fig 2). That lipoic acid, a vicinal SH
group-containing compound that may directly bind arsenic,9 was more effective (Fig 2, lane 4) than NAC (Fig 2, lane 6) in preventing PML/RAR- degradation suggests that lipoic acid competes with PML/RAR- in binding to As2O3 and may
prevent As2O3-induced structural changes in
PML/RAR-. The high sensitivity to As2O3 degradation of the nucleoplasmic fraction of PML and PML/RAR-, but
not other proteins in the nuclear dense body,32 may be due to their high content of vicinal cysteines in ring fingers and B-box
motifs7 to which As2O3 may bind
with high affinity.9
GSH is the major autooxidant of the cells and functions to scavenge
free radicals and to detoxify toxins and chemotherapeutic agents.33,34 GSH can bind arsenic from attacking its target by formation of a transient As(GS)3 complex.18
Many enzymes and factors modulate the level of GSH. It is known that
the glutathione transferase GST- , an enzyme involved in metabolic
detoxification of a variety of xenobiotics, is increased in an
arsenic-resistant CHO cell line.14,35 We also found that
the MDA-MB-468, a breast cancer line with low GST activity, is
sensitive to very low concentrations of As2O3
(Table 4).36 Glutathione peroxidase is lower
in another CHO subclone than in the parent cells and is less resistant
to arsenite-induced genotoxicity.37 Drugs that inhibit the
activity of GSH peroxidase increase the efficacy of the apoptotic
activity of As2O3 in malignant lymphocytic cell
lines (manuscript in preparation). Multidrug-resistant
protein (MRP) is important in determining the sensitivity of many
natural toxins, including sodium arsenite, and cotransports GSH and
xenobiotics from the cell.38,39 The relative importance of
adenosine triphosphate (ATP)-dependent membrane export by MRP and the
GSH detoxification pathway in determining sensitivity to
As2O3 remains to be determined. Meanwhile,
using subtractive hybridization, it was found that metallothionine and thioredoxin reductase, two other detoxification system-related factors,40,41 are upregulated in arsenic treated NB4 cells (M. Mao, personal communication, 1997).
We have shown that compounds that lower the GSH content potentiate the
apoptotic effect of As2O3, whereas protecting
or increasing the GSH level protects the cells from the apoptotic
effect of As2O3 (Figs 2 and 3). NB4 cells are
protected from the apoptotic effect of As2O3 if
treated with the antioxidant NAC, which preserves the GSH content (Fig
2A). On the other hand, BSO, which inhibits the synthesis of
glutamyl-cysteine, lowers the GSH content of NB4 cells and potentiates
the apoptotic effect of As2O3. In BSO-treated cells, 1 µmol/L As2O3 induces apoptosis in
70% of the cells in only 12 hours of treatment, and less sensitive
cell lines like su-DHL-4 and HL-60 become as sensitive as NB4 (Fig 3).
Ascorbic acid, which can act as a major antioxidant can protect cells
from oxygen radicals formed by 4-HPR,42
curcumin,43 and other agents44,45 that induce
apoptosis. In contrast, ascorbic acid can induce apoptosis
alone46 or in combination with agents in other cell
systems.47 In HL-60 cells, dehydroascorbic acid but not
ascorbic acid is transported via glucose transporters and is coupled to
its intracellular reduction to ascorbic acid.48 In our
studies, ascorbic acid in combination with
As2O3 has a potentiating effect due to its
capacity to undergo autooxidation resulting in the formation of
H2O2 which potentiates the effect of
As2O3 (Table 1). This assumption is fortified
by our findings that in the presence of catalase, ascorbic acid does
not enhance As2O3 and the combined treatment of
As2O3 and H2O2 is
synergistic for the induction of apoptosis (Table 2). Thus, the balance
between GSH and H2O2 may determine the
apoptotic effect of As2O3 in leukemic cells.
However, ascorbic acid did not potentiate the effect of As2O3 on the colony formation capacity of
normal hematopoietic cells (Figs 6 and 7). The synergistic effect of
As2O3 with ascorbic acid manifested itself also
in one epithelial mammary carcinoma line T47D, whereas normal breast or
embryo fibroblasts were insensitive to As2O3
and not sensitized by the addition of ascorbic acid (Table 4). This
selective action of ascorbic acid may be partially due to the low
concentration of catalase in some malignant cells.49,50 Thus, it should be possible to use low concentration of
As2O3 with ascorbic acid to selectively induce
apoptosis in some malignant cells without causing severe side effect in
normal tissues. We tested this possibility in an in vivo mouse model.
We found that the combined effect of As2O3 and
ascorbic acid increased the survival time of mice injected with
P388D-lymphoma cells, whereas single-agent treatment did not influence
survival (Table 5).
In summary the redox system of the cell and the capacity to eliminate
reactive oxygen species determine the efficacy of
As2O3. It is noteworthy that normal cells in
general are more efficient in eliminating reactive oxygen species than
malignant cells. Thus, it seems that malignant cells with low GSH
levels or GST activity should be sensitive to
As2O3 or the combined treatment of
As2O3 and ascorbic acid.
| |
ACKNOWLEDGMENT |
We appreciate the technical assistance of Yelena Galperin for bone
marrow colony assays and the guidance of Dr George Acs throughout these
studies.
| |
FOOTNOTES |
Submitted February 19, 1998;
accepted August 24, 1998.
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 Samuel Waxman, MD, Division of
Neoplastic Diseases, Department of Medicine, Mount Sinai Medical
Center, Box 1178, One Gustave L. Levy Place, New York, NY 10029-6547.
| |
REFERENCES |
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K. Davison, K. K. Mann, S. Waxman, and W. H. Miller Jr
JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells
Blood,
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[Abstract]
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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
Clin. Cancer Res.,
March 15, 2004;
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[Abstract]
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A. M. Evens, S. Prachand, B. Shi, M. Paniaqua, L. I. Gordon, and R. B. Gartenhaus
Imexon-Induced Apoptosis in Multiple Myeloma Tumor Cells Is Caspase-8 Dependent
Clin. Cancer Res.,
February 15, 2004;
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[Abstract]
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C. Fernandez, A. M. Ramos, P. Sancho, D. Amran, E. de Blas, and P. Aller
12-O-Tetradecanoylphorbol-13-acetate May Both Potentiate and Decrease the Generation of Apoptosis by the Antileukemic Agent Arsenic Trioxide in Human Promonocytic Cells: REGULATION BY EXTRACELLULAR SIGNAL-REGULATED PROTEIN KINASES AND GLUTATHIONE
J. Biol. Chem.,
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[Abstract]
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J. Yi, J. Yang, R. He, F. Gao, H. Sang, X. Tang, and R. D. Ye
Emodin Enhances Arsenic Trioxide-Induced Apoptosis via Generation of Reactive Oxygen Species and Inhibition of Survival Signaling
Cancer Res.,
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[Abstract]
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T. Ikeda, Y. Nakata, F. Kimura, K. Sato, K. Anderson, K. Motoyoshi, M. Sporn, and D. Kufe
Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
Mol. Cancer Ther.,
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[Abstract]
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I. V. Lebedeva, Z.-Z. Su, D. Sarkar, S. Kitada, P. Dent, S. Waxman, J. C. Reed, and P. B. Fisher
Melanoma Differentiation Associated Gene-7, mda-7/Interleukin-24, Induces Apoptosis in Prostate Cancer Cells by Promoting Mitochondrial Dysfunction and Inducing Reactive Oxygen Species
Cancer Res.,
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[Abstract]
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J. McCafferty-Grad, N. J. Bahlis, N. Krett, T. M. Aguilar, I. Reis, K. P. Lee, and L. H. Boise
Arsenic trioxide uses caspase-dependent and caspase-independent death pathways in myeloma cells
Mol. Cancer Ther.,
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[Abstract]
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E. Raffoux, P. Rousselot, J. Poupon, M.-T. Daniel, B. Cassinat, R. Delarue, A.-L. Taksin, D. Rea, A. Buzyn, A. Tibi, et al.
Combined Treatment With Arsenic Trioxide and All-Trans-Retinoic Acid in Patients With Relapsed Acute Promyelocytic Leukemia
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[Abstract]
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S. Sturlan, M. Baumgartner, E. Roth, and T. Bachleitner-Hofmann
Docosahexaenoic acid enhances arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant HL-60 cells
Blood,
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[Abstract]
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R. Nasr, A. Rosenwald, M. E. El-Sabban, B. Arnulf, P. Zalloua, Y. Lepelletier, F. Bex, O. Hermine, L. Staudt, H. de The, et al.
Arsenic/interferon specifically reverses 2 distinct gene networks critical for the survival of HTLV-1-infected leukemic cells
Blood,
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[Abstract]
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T. Kanzawa, Y. Kondo, H. Ito, S. Kondo, and I. Germano
Induction of Autophagic Cell Death in Malignant Glioma Cells by Arsenic Trioxide
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G.-Q. Chen, L. Zhou, M. Styblo, F. Walton, Y. Jing, R. Weinberg, Z. Chen, and S. Waxman
Methylated Metabolites of Arsenic Trioxide Are More Potent Than Arsenic Trioxide as Apoptotic but not Differentiation Inducers in Leukemia and Lymphoma Cells
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D. Douer, W. Hu, S. Giralt, M. Lill, and J. DiPersio
Arsenic Trioxide (Trisenox(R)) Therapy for Acute Promyelocytic Leukemia in the Setting of Hematopoietic Stem Cell Transplantation
Oncologist,
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L. Vernhet, N. Allain, M. Le Vee, F. Morel, A. Guillouzo, and O. Fardel
Blockage of Multidrug Resistance-Associated Proteins Potentiates the Inhibitory Effects of Arsenic Trioxide on CYP1A1 Induction by Polycyclic Aromatic Hydrocarbons
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N. J. Bahlis, J. McCafferty-Grad, I. Jordan-McMurry, J. Neil, I. Reis, M. Kharfan-Dabaja, J. Eckman, M. Goodman, H. F. Fernandez, L. H. Boise, et al.
Feasibility and Correlates of Arsenic Trioxide Combined with Ascorbic Acid-mediated Depletion of Intracellular Glutathione for the Treatment of Relapsed/Refractory Multiple Myeloma
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L. Staleva, P. Manga, and S. J. Orlow
Pink-eyed Dilution Protein Modulates Arsenic Sensitivity and Intracellular Glutathione Metabolism
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[Abstract]
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A. Verma, M. Mohindru, D. K. Deb, A. Sassano, S. Kambhampati, F. Ravandi, S. Minucci, D. V. Kalvakolanu, and L. C. Platanias
Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to Arsenic Trioxide
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R. Furumai, A. Matsuyama, N. Kobashi, K.-H. Lee, M. Nishiyama, H. Nakajima, A. Tanaka, Y. Komatsu, N. Nishino, M. Yoshida, et al.
FK228 (Depsipeptide) as a Natural Prodrug That Inhibits Class I Histone Deacetylases
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T. Hayashi, T. Hideshima, M. Akiyama, P. Richardson, R. L. Schlossman, D. Chauhan, N. C. Munshi, S. Waxman, and K. C. Anderson
Arsenic Trioxide Inhibits Growth of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment
Mol. Cancer Ther.,
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[Abstract]
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Y. Jing, L. Xia, and S. Waxman
Targeted removal of PML-RARalpha protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia
Blood,
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[Abstract]
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W. H. Miller Jr., H. M. Schipper, J. S. Lee, J. Singer, and S. Waxman
Mechanisms of Action of Arsenic Trioxide
Cancer Res.,
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[Abstract]
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J. L. Slack, S. Waxman, G. Tricot, M. S. Tallman, and C. D. Bloomfield
Advances in the Management of Acute Promyelocytic Leukemia and Other Hematologic Malignancies with Arsenic Trioxide
Oncologist,
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[Abstract]
[Full Text]
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W. H. Miller Jr.
Molecular Targets of Arsenic Trioxide in Malignant Cells
Oncologist,
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[Abstract]
[Full Text]
[PDF]
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M. A. Hussein
Nontraditional Cytotoxic Therapies for Relapsed/Refractory Multiple Myeloma
Oncologist,
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[Abstract]
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M. O'Dwyer
Multifaceted Approach to the Treatment of Bcr-Abl-Positive Leukemias
Oncologist,
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[Abstract]
[Full Text]
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R. B. Gartenhaus, S. N. Prachand, M. Paniaqua, Y. Li, and L. I. Gordon
Arsenic Trioxide Cytotoxicity in Steroid and Chemotherapy-resistant Myeloma Cell Lines: Enhancement of Apoptosis by Manipulation of Cellular Redox State
Clin. Cancer Res.,
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K. Dvorakova, C. M. Payne, M. E. Tome, M. M. Briehl, M. A. Vasquez, C. N. Waltmire, A. Coon, and R. T. Dorr
Molecular and Cellular Characterization of Imexon-resistant RPMI8226/I Myeloma Cells
Mol. Cancer Ther.,
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[Abstract]
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D. Cen, R. I. Gonzalez, J. A. Buckmeier, R. S. Kahlon, N. B. Tohidian, and F. L. Meyskens Jr
Disulfiram Induces Apoptosis in Human Melanoma Cells: A Redox-related Process
Mol. Cancer Ther.,
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J. M. Grad, N. J. Bahlis, I. Reis, M. M. Oshiro, W. S. Dalton, and L. H. Boise
Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells
Blood,
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805 - 813.
[Abstract]
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H. Maeda, S. Hori, H. Nishitoh, H. Ichijo, O. Ogawa, Y. Kakehi, and A. Kakizuka
Tumor Growth Inhibition by Arsenic Trioxide (As2O3) in the Orthotopic Metastasis Model of Androgen-independent Prostate Cancer
Cancer Res.,
July 1, 2001;
61(14):
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[Abstract]
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O. Sordet, C. Rebe, I. Leroy, J.-M. Bruey, C. Garrido, C. Miguet, G. Lizard, S. Plenchette, L. Corcos, and E. Solary
Mitochondria-targeting drugs arsenic trioxide and lonidamine bypass the resistance of TPA-differentiated leukemic cells to apoptosis
Blood,
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3931 - 3940.
[Abstract]
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K. Dvorakova, C. N. Waltmire, C. M. Payne, M. E. Tome, M. M. Briehl, and R. T. Dorr
Induction of mitochondrial changes in myeloma cells by imexon
Blood,
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[Abstract]
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J. Dai, R. Shen, M. Sumitomo, J. S. Goldberg, Y. Geng, D. Navarro, S. Xu, J. A. Koutcher, M. Garzotto, C. T. Powell, et al.
Tumor-Suppressive Effects of Neutral Endopeptidase in Androgen-independent Prostate Cancer Cells
Clin. Cancer Res.,
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S. Waxman and K. C. Anderson
History of the Development of Arsenic Derivatives in Cancer Therapy
Oncologist,
April 1, 2001;
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3 - 10.
[Abstract]
[Full Text]
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A. J. Murgo
Clinical Trials of Arsenic Trioxide in Hematologic and Solid Tumors: Overview of the National Cancer Institute Cooperative Research and Development Studies
Oncologist,
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[Abstract]
[Full Text]
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Y. Jing, L. Wang, L. Xia, G.-q. Chen, Z. Chen, W. H. Miller, and S. Waxman
Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo
Blood,
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M. J. McCabe Jr., K. P. Singh, S. A. Reddy, B. Chelladurai, J. G. Pounds, J. J. Reiners Jr., and J. C. States
Sensitivity of Myelomonocytic Leukemia Cells to Arsenite-Induced Cell Cycle Disruption, Apoptosis, and Enhanced Differentiation Is Dependent on the Inter-Relationship between Arsenic Concentration, Duration of Treatment, and Cell Cycle Phase
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K. Hossain, A. A. Akhand, M. Kato, J. Du, K. Takeda, J. Wu, K. Takeuchi, W. Liu, H. Suzuki, and I. Nakashima
Arsenite Induces Apoptosis of Murine T Lymphocytes Through Membrane Raft-Linked Signaling for Activation of c-Jun Amino-Terminal Kinase
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P. Borst, R. Evers, M. Kool, and J. Wijnholds
A Family of Drug Transporters: the Multidrug Resistance-Associated Proteins
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G. J. Roboz, S. Dias, G. Lam, W. J. Lane, S. L. Soignet, R. P. Warrell Jr, and S. Rafii
Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis
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W. H. Park, J. G. Seol, E. S. Kim, J. M. Hyun, C. W. Jung, C. C. Lee, B. K. Kim, and Y. Y. Lee
Arsenic Trioxide-mediated Growth Inhibition in MC/CAR Myeloma Cells via Cell Cycle Arrest in Association with Induction of Cyclin-dependent Kinase Inhibitor, p21, and Apoptosis
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C. Perkins, C. N. Kim, G. Fang, and K. N. Bhalla
Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-xL
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Y. Jing, J. Dai, R. M.E. Chalmers-Redman, W. G. Tatton, and S. Waxman
Arsenic Trioxide Selectively Induces Acute Promyelocytic Leukemia Cell Apoptosis Via a Hydrogen Peroxide-Dependent Pathway
Blood,
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A. Melnick and J. D. Licht
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G. Kroemer and H. de The
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S. V. Kala, M. W. Neely, G. Kala, C. I. Prater, D. W. Atwood, J. S. Rice, and M. W. Lieberman
The MRP2/cMOAT Transporter and Arsenic-Glutathione Complex Formation Are Required for Biliary Excretion of Arsenic
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Top
Abstract
Introduction