Pharmacologic doses of ascorbate act as a prooxidant
and decrease growth of aggressive tumor xenografts
Qi Chen*†, Michael Graham Espey*†‡, Andrew Y. Sun*, Chaya Pooput§, Kenneth L. Kirk§, Murali C. Krishna¶,
Deena Beneda Khosh?, Jeanne Drisko?, and Mark Levine*‡
*Molecular and Clinical Nutrition Section and§Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,
and¶Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and?Program in Integrative Medicine,
University of Kansas Medical Center, Kansas City, KS 66160
Edited by Bruce N. Ames, Children’s Hospital Oakland Research Institute, Oakland, CA, and approved June 6, 2008 (received for review May 1, 2008)
Ascorbic acid is an essential nutrient commonly regarded as an
antioxidant. In this study, we showed that ascorbate at pharma-
cologic concentrations was a prooxidant, generating hydrogen-
peroxide-dependent cytotoxicity toward a variety of cancer cells in
vitro without adversely affecting normal cells. To test this action in
vivo, normal oral tight control was bypassed by parenteral ascor-
ing glioblastoma xenografts showed that a single pharmacologic
dose of ascorbate produced sustained ascorbate radical and hy-
drogen peroxide formation selectively within interstitial fluids of
tumors but not in blood. Moreover, a regimen of daily pharmaco-
logic ascorbate treatment significantly decreased growth rates of
ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P <
0.001) tumors established in mice. Similar pharmacologic concen-
trations were readily achieved in humans given ascorbate intra-
venously. These data suggest that ascorbate as a prodrug may
have benefits in cancers with poor prognosis and limited thera-
cancer ? hydrogen peroxide ? oxidation ? free radical ? vitamin C
viewpoint is that ascorbate serves as an antioxidant and in-
creased intake from either foods or dietary supplements might
promote good health (1). Cancer chemoprevention studies have
used this antioxidant rationale to examine a putative inverse
association between tumor incidence and ascorbate ingestion (2,
3). In contrast to this line of investigation, we have tested the
hypothesis that pharmacologic concentrations of ascorbate may
engender a prooxidant cytotoxic state within tumors. In our
initial in vitro experiments, we observed hydrogen peroxide
(H2O2)-dependent cytotoxicity after ascorbate exposure (EC50
? 4 mM) in five cancer cell lines, whereas normal cells were
resistant (4). The in vivo pharmacokinetics of ascorbate treat-
ment was subsequently determined in rats (5). These dosing and
biodistribution data in rodents showed that oral ascorbate
administration produced concentrations that cannot exceed 0.2
mM in plasma and extracellular fluids because of physiologic
tight control, similar to mechanisms that exist in humans (6–8).
Pharmacologic concentrations of ascorbate (?0.2 mM) in body
fluids could be attained only when oral tight control mechanisms
were bypassed by parenteral (i.v., i.p.) ascorbate administration
routes. Pharmacologic ascorbate concentrations in plasma re-
sulted in the formation of both ascorbate radical and H2O2in
extracellular fluid of the tissue parenchyma (5). On the basis of
these data, the efficacy of parenteral ascorbate administration
on tumor growth in vivo was examined by using the dose-toxicity
relationships of ascorbate in numerous types of cancer cells in
itamin C (ascorbate) is an essential micronutrient used as a
co-factor by numerous biosynthetic enzymes. An additional
Range of Cancer Cell Sensitivity to Ascorbate-Derived Hydrogen
Peroxide. An extensive panel of 43 tumor and 5 normal cell lines
were exposed to ascorbate in vitro for ?2 h to mimic clinical
pharmacokinetics, and the effective concentration that de-
creased survival 50% (EC50) was determined. EC50was ?10 mM
for 75% of tumor cells tested, whereas cytotoxicity was not
evident in normal cells with ?20 mM ascorbate (Fig. 1A). The
addition of catalase to the medium ameliorated death of ovarian
carcinoma (Ovcar5), pancreatic carcinoma (Pan02), and glio-
blastoma (9L) cells exposed to 10 mM ascorbate (1 h), indicating
cytotoxicity was mediated by H2O2(Fig. 1B), which is consistent
with previous work on a more limited sampling of cancer cell
types (4, 9).
Pharmacological Ascorbate Treatment Decreases Tumor Growth.
Given their relative sensitivity, the efficacy of pharmacologic
ascorbate administration on the growth of Ovcar5, Pan02, and
9L tumors was examined in nude mice. The acidity of ascorbate
solutions was neutralized to pH 7 with sodium hydroxide. A
maximum tolerated dose for ascorbate was limited by potential
stress from osmotic imbalance after injection into the peritoneal
cavity. A treatment dose of 4 g ascorbate/kg body weight either
once or twice daily did not produce any discernible adverse
effects. Treatment commenced after tumors reached a palpable
size of 5–7 mm in diameter.
Xenograft experiments showed that parenteral ascorbate as
the only treatment significantly decreased both tumor growth
and weight by 41–53% (P ? 0.04–0.001) for Ovcar5, Pan02, and
9L tumors (Fig. 2 A–F). Metastases, present in ?30% of 9L
glioblastoma controls, were absent in ascorbate-treated animals
(data not shown).
In Situ Analysis Shows Prooxidant Metabolism of Ascorbate at Phar-
macological Concentrations Is Achievable in Human Subjects. To
explore potential mechanisms underlying ascorbate action in
vivo, blood samples and interstitial fluids from s.c. and 9L tumor
sites were obtained by microdialysis in athymic mice. Parenteral
administration of a single ascorbate dose (4 g per kilogram of
and J.D. performed research; C.P., K.L.K., and M.C.K. contributed new reagents/analytical
tools; Q.C., M.G.E., C.P., K.L.K., M.C.K., J.D., and M.L. analyzed data; and M.G.E. and M.L.
wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
†Q.C. and M.G.E. contributed equally to this work.
‡To whom correspondence may be addressed at: Molecular and Clinical Nutrition Section,
National Institute of Diabetes and Digestive and Kidney Diseases, 10/4D52, 9000 Rockville
Pike, National Institutes of Health, Bethesda, MD 20892. E-mail: firstname.lastname@example.org or mark.
© 2008 by The National Academy of Sciences of the USA
www.pnas.org?cgi?doi?10.1073?pnas.0804226105 PNAS ?
August 12, 2008 ?
vol. 105 ?
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body weight) increased ascorbate in both blood and tissue sites
?150-fold from a baseline of ?0.2 mM to peak concentrations
of ?30 mM after 90–180 min (Fig. 3A). Treatment increased
ascorbate radical in the extracellular fluid of both 9L tumors and
the s.c. space from ?10 nM to 500 nM and higher, but blood
concentrations did not exceed 50 nM (Fig. 3B). Ascorbate
radical concentration as a function of ascorbate concentration
was displayed for all fluids and time points, and previous data
were added from studies of rats given lower ascorbate doses (Fig.
3C) (5). The relationships were strikingly consistent in the two
species and provide key evidence that with pharmacologic
ascorbate concentrations, ascorbate radical increased selectively
in extracellular fluids but not in blood. A rapid and sustained
increase in H2O2was detected within tumor extracellular fluids
within 30 min of parenteral ascorbate administration, achieving
a plateau of 150 ?M (Fig. 3D). Clinical relevance of pharma-
cokinetics data were investigated in human subjects who re-
ceived escalating doses of i.v. ascorbate as part of an exploratory
treatment protocol. Peak plasma concentrations of ascorbate
approached 30 mM (Fig. 3E), similar to concentrations observed
in mice given parenteral ascorbate (Fig. 3A).
These preclinical data provide a firm basis for advancing phar-
macologic ascorbate in cancer treatment to humans. The tumor
xenograft results are especially noteworthy because ascorbate,
considered a nutrient, was used here only as a single-agent drug.
Pharmacologic concentrations of ascorbate decreased tumor
volumes 41–53% in diverse cancer types known for both their
aggressive growth and limited treatment options.
Ascorbate has a unique history in cancer treatment. Interest
peaked over 30 years ago when retrospective data indicating
possible benefit of high-dose ascorbate for patients with cancer
were published (10, 11). Subsequent double-blind placebo-
controlled trials showing no benefit were considered definitive,
and ascorbate treatment was dismissed by conventional oncolo-
gists (12–14). We revisited the controversy of ascorbate in cancer
therapy in light of several new observations. First, it was recog-
nized that ascorbate was administered both intravenously and
orally in the retrospective studies but only orally in the double-
blind trials (15). Second, clinical and pharmacokinetics studies
within the past 12 years indicate that oral ascorbate produces
concentrations in plasma and tissue that are tightly controlled
(?0.2 mM) (6–8). Our studies in rats demonstrated that phar-
macologic concentrations of ascorbate in plasma (?0.2 mM)
could be achieved only by circumventing oral tight control with
parenteral administration (5). Third, complementary and alter-
native medicine practitioners continue to administer high-dose
ascorbate off label, without apparent toxicity when patients are
properly screened for normal renal function and absence of
glucose-6-phosphate dehydrogenase deficiency, iron overload,
and oxalate nephropathy (8, 14, 15). With such screening, data
from a recent Phase I study show that i.v. ascorbate did not have
adverse effects (16). These data coupled with the possibility
of benefit (17) suggested that further rigorous studies were
Our findings showed that pharmacologic ascorbic acid con-
centrations were cytotoxic to many types of cancer cells in vitro
(Fig. 1A) and significantly impeded tumor progression in vivo
without toxicity to normal tissues (Fig. 3). The amelioration of
ascorbate cytotoxicity in vitro by the addition of catalase was
consistent among sensitive cancer cells (Fig. 1B) and points
unambiguously to H2O2generation in the extracellular medium
(4). Hydrogen peroxide cytotoxicity is promiscuous in its action,
compromising membranes, glucose metabolism, and DNA in-
tegrity (18). Variation in sensitivity among cancer cells may be
related to the complex networks that H2O2acts on combined
with the range of functional mutations intrinsic to each cancer
cell line, which are not present in normal cells (EC50? 20 mM)
(Fig. 1A). Although the molecular basis for the relative resis-
% viable cells
(1 ? 104) in logarithmic growth phase were cultured in recommended growth
pH 7) for 2 h and washed and cultured for an additional 24–48 h in growth
medium in the absence of ascorbate. EC50values indicate the concentration of
ascorbate that reduced survival by 50% determined by viability assays as previ-
mM) ameliorated cytoxicity equivalently for all cells tested (E). Data in A and B
represent mean values of six determinations ? SD.
Relative cytotoxicity of ascorbate on cancer and normal cells. (A) Cells
www.pnas.org?cgi?doi?10.1073?pnas.0804226105 Chen et al.
data support that pharmacologic ascorbate concentrations,
which can readily be achieved in humans (Fig. 3E), diminished
growth of several aggressive cancer types in mice (Fig. 2) without
causing apparent adverse effects.
We observed that ascorbate radical was an essential interme-
diate in H2O2generation from pharmacologic ascorbate (Fig. 4).
Ascorbate radical concentrations in extracellular fluids of both
mice and rats were evident over a wide dose range of ascorbate,
reaching a steady-state plateau of ?500 nM at tissue ascorbate
concentrations of ?20 mM. Despite corresponding ascorbate con-
centrations in blood, minimal ascorbate radical and no H2O2were
evident (5) (Fig. 3). These data suggest that the lifetimes of
ascorbate radical and H2O2in blood are limited to below the
detection limit, likely because of the predominance of erythro-
cyte peroxidase capacity (18). Data generated using microdialy-
sis technique show that the putative metallocatalyst(s) for the
generation of ascorbate radical and H2O2 was present within
Our previous work suggested that catalytic activity in serum was
mediated by a protein (or proteins), because activity was heat-
labile and between 10 and 30 kDa in size (4). Ascorbate is a
reducing cofactor for a select small group of metal-centered
enzymes (19, 20). Pharmacologic concentrations of ascorbate
may react with a larger set of metallocatalysts with higher KMs
for ascorbate that otherwise are not engaged in normal biolog-
ical conditions. This degeneration toward increased nonspecific
reactions with pharmacologic ascorbate, with the subsequent
formation of H2O2, may underlie the physiologic basis of tight
control in ascorbate homeostasis.
It was notable that the tumor parenchyma experienced an
early and sustained increase in H2O2after ascorbate treatment
relative to s.c. sites (Fig. 3D). This finding may be because of
either an enhanced formation or decreased destruction of H2O2
within tumor intersitium relative to normal extracellular fluid.
These intratumoral H2O2concentrations of ?125 ?M persisted
for ?3 h after ascorbate administration, similar to endogenous
days of treament (4g/kg i.p. twice daily)
ascorbate, n = 13
saline, n = 15
tumor volume (mm3)
saline, n = 9
ascorbate, n = 10
tumor volume (mm3)
days of treament (4g/kg i.p. daily)
Pan02, day 13
tumor weight (mg)
days of treament (4g/kg i.p. twice daily)
saline, n = 18
ascorbate, n = 18
tumor volume (mm3)
9L, day 12
tumor weight (mg)
Ovcar5, day 30
tumor weight (mg)
commenced with either ascorbate (4 g per kilogram of body weight) or osmotically equivalent saline by i.p. injection as indicated. Data (? SEM) show growth
curves and final tumor weight with either saline (?) or ascorbate (■) treatments in mice bearing Ovcar5 (A and B), Pan02 (C and D) and 9L (E and F) tumors. P
values were calculated by unpaired t-test:*, P ? 0.01;**, P ? 0.005;***, P ? 0.001.
Impact of pharmacological ascorbate on tumor growth. Tumors were grown in the flanks of athymic mice to a volume of ?50 ? 10 mm3, and treatment
Chen et al.PNAS ?
August 12, 2008 ?
vol. 105 ?
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levels evident in dermal wound sites 2–5 d after injury (21).
Although H2O2formation may be a trigger for angiogenesis (22,
23), normal wound healing follows a defined temporal progres-
sion and resolution. In contrast to this healing process, our
regimen of daily pharmacologic ascorbate treatment produced
episodic and chronic H2O2formation, which in the context of the
tumor milieu manifested as an overall diminished tumor growth
rate (Fig. 2). Of note, the tumoricidal effect of daily pharma-
cologic ascorbate treatment was mechanistically similar to the
effects observed in other investigations that used adenoviral-
driven overexpression of the extracellular isoform of superoxide
dismutase in pancreatic tumors (24). Both approaches increased
interstitial H2O2concentrations, leading to a comparable sup-
pression of cancer growth.
Pharmacologic ascorbate is readily available, inexpensive, and
without apparent toxicity when used with proper screening.
Moreover, substantial off-label administration of ascorbate al-
ready exists within the complementary medicine community.
Figure 3E shows that pharmacologic plasma ascorbate concen-
trations similar to those showing efficacy in tumor-bearing mice
can be attained in humans. Although our preclinical mouse data
showed that tumor growth was significantly decreased (Fig. 2),
the use of pharmacologic ascorbate as a single agent was not
curative. As modalities in cancer are often combined, these data
suggest that pharmacologic ascorbate in combination with other
therapies deserves further exploration for treatment of cancers
permission from Chen Q, et al. (5) (Copyright 2007)]. (D) Formation of H2O2in
s.c. (?) or tumor (■) extracellular fluid. (E) Peak plasma concentrations of
ascorbate in human subjects who received escalating doses of i.v. ascorbate.
030 6090120 150 180
blood, n = 21
subcutaneous, n =21
9L tumor, n = 21
0 30 6090120150180
blood, n = 8
subcutaneous, n = 11
9L tumor, n = 11
ascorbate radical (nM)
ascorbate radical (nM)
subcutaneous, n = 9
9L tumor, n = 9
H2O2 ( M)
i.v. ascorbate dose (g)
plasma ascorbate (mM)
Mice were anesthetized and maintained for microdialysis as previously de-
scribed in Materials and Methods. Separate probes implanted into either
A single dose of ascorbate (4 g per kilogram of body weight, pH 7) was given
by i.p. injection at 0 min, and probe eluates were collected simultaneously
from each site in 30-min intervals. Blood was collected from the tail vein into
heparinized hematocrit tubes, and analytes were determined as single point
measures every 30 min. (A and B) Ascorbate and ascorbate radical concentra-
tions in blood (F), s.c. (?), and tumor (■) extracellular fluids. (C) Ascorbate
radical in blood (F), s.c. (?), or tumor (■) extracellular fluid as a function of
ascorbate concentrations for all time points (? SEM) are shown. (Inset) Pre-
vious data (dashed box) were added from studies of rat-administered
Real-time quantification of ascorbate prodrug metabolism in vivo.
ascorbate. Ascorbate (AA) distributes from the blood to the tumor extracel-
lular fluid compartments after i.v. administration. In the tumor interstitium,
ascorbate is oxidized to ascorbate radical (AA•) by a metalloprotein catalyst
and ultimately the tumorcidal effector H2O2.In blood, these reactions are
minimized (4, 5).
Proposed mechanism for tumorcidal actions of pharmacological
www.pnas.org?cgi?doi?10.1073?pnas.0804226105Chen et al.
that otherwise have poor outcomes, such as pancreatic and
ovarian carcinomas and glioblastoma.
Materials and Methods
Cells and Cytoxicity Assessment. Cell lines were either purchased from Amer-
Health), William DeGraff (National Cancer Institute, National Institutes of
Health), Peter Eck (National Cancer Institute, National Institutes of Health),
Corinne Griguer (University of Alabama, Birmingham, AL), Lucia Martiniova
(National Institute of Child Helath and Human Development, National Insti-
tutes of Health), Marsha Merrill (National Institute of Neurological Disorders
and Stroke, National Institutes of Health), James Mitchell (National Cancer
National Institutes of Health), Anthony Sandler (Children’s National Medical
Center, Washington, DC), Emily Shacter (Center for Biologics Evaluation and
Research, United States Food and Drug Administration), Lyuba Varticovski
(National Cancer Institute, National Institutes of Health), and Lalage Wake-
field (National Cancer Institute, National Institutes of Health). Cells (1 ? 104)
in logarithmic growth phase were cultured at 37°C in 5% CO2/95% air in
recommended growth media containing 10% FCS and exposed to serial
additional 24–48 h in growth medium in the absence of ascorbate. Ascorbic
before use. EC50values indicate the concentration of ascorbate that reduced
survival by 50% determined by viability assays as previously described (4, 25).
Human lymphocyte and monocytes were freshly elutriated from peripheral
blood donors. EC50values for 13 of 43 cells in Fig. 1A were previously shown
(4). Catalase (600 units/ml; Sigma) was prepared immediately before use.
Xenograft and Treatment Procedures. Tumor cells (Ovcar5, 5 ? 106; Pan02, 1 ?
flanks of female athymic mice (Ncr-nu/nu aged 5–8 weeks). When tumor
volume reached 25–50 mm3, treatment commenced with ascorbate (4 g per
kilogram of body weight) by i.p. injection. Ascorbate was prepared as 1 M
stock solution in sterile water adjusted to pH 7 with NaOH. Control mice
received an identical regimen of osmotically equivalent saline solution. Lon-
gitudinal tumor volume was calculated from caliper measurements using
killed with final tumor weight and metastases assessed by gross necropsy.
In Situ Sample Acquisition. Mice were anesthetized and maintained for mi-
crodialysis as previously described (5) with the following modifications: sep-
arate probes (CMA/20 4 ? 0.5 mm, 20 kDa cutoff) were implanted into tumor
tissue (right flank) and s.c. spaces (left flank) and perfused (1 ?l/min) with
sterile 0.9% saline solution. After a 30-min baseline period, a single dose of
ascorbate (4 g per kilogram of body weight, pH 7) was given by i.p. injection
at 0 min and probe eluates were collected simultaneously from each site in
30-min intervals. Relative recovery of analytes through the probe membrane
was: ascorbate 12%, ascorbate radical 65%, and H2O220%. Blood was col-
determined as single point measures every 30 min.
Analytical Chemistry. Ascorbate and ascorbate radical concentrations in
plasma and microdialysates were determined by HPLC separation with elec-
trochemical detection and electron paramagnetic resonance, respectively, as
previously described (5). Formation of H2O2was determined by simultaneous
collection of dialysate into tubes containing peroxyxanthone (20 ?M) either
as previously described (5). Nonspecific background signal and low probe
relative recovery restricted the lower limit of sensitivity to 20 ?M.
Human Studies. Plasma ascorbic acid concentrations were measured in partic-
the University of Kansas (ClinicalTrials.gov registration numbers:
Kansas Human Subjects Committee, and written informed consent was ob-
tained from each participant. A single starting ascorbate dose of 15 g over 30
min at 0.5 g/min was infused with subsequent dose escalation of 25 g over 50
min, 50 g over 100 min, 75 g over 150 min, and 100 g over 200 min. Venous
blood samples (n ? 8, 4 at 100 g) were drawn at the completion of each
infusion, and plasma was immediately prepared and frozen to ?80°C until
ACKNOWLEDGMENTS. We thank all those who kindly shared their cell lines
with us. This research was supported in part by the Intramural Research
Program of the National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health.
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