The

Oncologist ®

Clinical Pharmacology
Commentary: Antioxidants for Cancer: New Tricks for an Old Dog?

NIMA SHARIFI

Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern

Medical Center, Dallas, Texas, USA

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Disclosures: Nima Sharifi: Research funding: Prostate Cancer Foundation
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from
commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer
reviewers.

ABSTRACT
Traditionally, the main focus of the importance of reac-
tive oxygen species (ROS) in oncology is that these spe-
cies induce DNA damage, leading to a predisposition to
cancer. However, it has recently been shown that ROS
may have an alternative activity, by modulating tumor
cell signaling. Moreover, tumor cell signaling mediated
by ROS is readily reversible upon treatment with anti-
oxidants. This emerging evidence on the molecular ef-
fects of antioxidants on tumor cells, along with the
evidence that the route of administration of antioxi-
dants in earlier clinical trials for cancer could not
achieve pharmacologically effective levels, suggests that
antioxidants may serve as bona fide signal transduction
modifiers for cancer. A re-examination of the current
evidence and further study is clearly warranted. The On-
cologist 2009;14:213–215

Over two decades ago, reports of a role for the utility of oxidants in combination with other treatments, such as che-
ascorbate for use in cancer [1] were effectively dismissed motherapy and radiation, which is beyond the scope of the
with the completion of two double-blind, placebo-con- discussion here [7, 8]. Recently, several preclinical studies
trolled clinical trials of oral ascorbate that showed no effect have suggested a critical role of reactive oxygen species
on survival in patients with advanced cancer [2, 3]. How- (ROS) for tumor signaling and growth, along with revers-
ever, later studies determined that the oral bioavailability ibility of these ROS-mediated mechanisms that is achiev-
with the doses used in those studies gave a much lower ex- able with antioxidants [9 –11]. This emerging evidence
posure than i.v. administration, which was done with earlier raises the question of whether we should revisit the issue of
nonrandomized trials that suggested a benefit [4]. Other a potential utility of antioxidants for cancer therapy.
studies have investigated a potential role for N-acetylcyste- Free radicals or ROS have a well-established role in the
ine (NAC) with or without vitamin A for the management initiation of cancer through effects on DNA damage that re-
of lung and head and neck cancers and have also not shown sult in mutations, leading to the activation of oncogenes and
efficacy [5]. However, oral administration of NAC, which loss of tumor suppressor gene function [12]. It is in this con-
was used in this study, largely undergoes first-pass metab- text that ROS are typically thought of in a link to cancer and
olism and is also scarcely bioavailable [6]. It should be in which antioxidants have been posited to play a potential
noted that numerous other studies have tested various anti- role in cancer chemoprevention. However, ROS also have
Correspondence: Nima Sharifi, M.D., Division of Hematology/Oncology, Department of Internal Medicine, University of Texas South-
western Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8852, USA. Telephone: 214-645-5910; Fax: 214-648-5915;
e-mail: nima.sharifi@utsouthwestern.edu Received October 6, 2008; accepted for publication February 2, 2009; first published online
in The Oncologist Express on March 5, 2009. ©AlphaMed Press 1083-7159/2009/$30.00/0 doi: 10.1634/theoncologist.2008-0219

The Oncologist 2009;14:213–215 www.TheOncologist.com

214
multiple and diverse effects on cell signaling [13]. For ex-
ample, ROS play a role in the activation of the c-myc onco-
gene [14] and the hypoxia inducible factor (HIF)-1
transcription factor [15], which are both critical tumor sig-
naling mechanisms that drive growth and proliferation.
These and other signaling pathways may be modified by in-
creasing or decreasing the intracellular levels of ROS. Re-
cent evidence suggests that ROS-dependent signals are
required for tumor growth and that altering levels of ROS
with antioxidants or pro-oxidants could modulate tumor
growth.
HIF-1 activation occurs under hypoxic conditions. Al-
though counterintuitive, hypoxia increases, rather than de-
creases, ROS, which are mechanistically required for the
inactivation of prolyl hydroxylases, leading to the stabiliza-
tion, accumulation, and activation of HIF-1 [15]. Hypoxia-
induced HIF-1 activity was recently found in mouse models
to be partially reversible upon treatment with NAC [9] in
prostate and lymphoid-derived tumors, further suggesting
the importance of the ROS-dependent mechanism of HIF-1
accumulation and activation. Moreover, Myc-mediated tu-
morigenesis in a mouse tumor model, which requires HIF-1
activity, is largely reversible upon treatment with NAC and
in separate experiments with ascorbate [9]. These findings
suggest that reversal of HIF-1 activity with antioxidants is
achievable in vivo to such an extent that is sufficient to in-
duce antitumor activity. They also suggest that the role of
ROS in driving tumor growth is not limited to a mechanism
involving DNA damage and genomic instability.
A second recent study showed that, in addition to hy-
poxic stimulation of ROS, ROS generation also occurs
through other mechanisms and that ROS is involved in reg-
ulating tumor metastasis [10]. Mutations in respiratory
complex I in mitochondrial DNA occur in tumors that are
highly metastatic. These mutations result in the production
of high levels of ROS. Transfer of mitochondria with these
mutations from highly metastatic tumors conferred meta-
static potential to tumors with previously low metastatic
capability and normal complex I activity. Moreover,
mitochondria with normal complex I activity from cells
with low metastatic capability suppressed metastases from
previously highly metastatic tumors [10]. This suggests that
the metastatic “trait” in these cells follows mutant complex
I and excessive ROS production. Furthermore, cells with
mutant complex I had higher levels of HIF-1 than those
with normal complex I, under both normoxic and hypoxic
conditions. Pretreatment of tumor cells with NAC before
injection into mice, as well as direct treatment of mice in-
oculated with these cells, markedly inhibited metastatic ac-
tivity. These findings demonstrate that ROS generation in
cancer cells drives cell signaling that is critical to metastatic
Antioxidants for Cancer
activity and that direct targeting of ROS with antioxidants
may reverse this process.
A third recent study showed that the spectrum of antitu-
mor activity in mouse models is broad, with ascorbate
blunting the growth of several types of tumors, including
ovarian carcinoma, pancreatic carcinoma, and glioblastoma
[11]. Importantly, the concentrations required for activity
are similar to those achievable in humans treated with i.v.
ascorbate [11]. Surprisingly, this line of investigation
showed that hydrogen peroxide concentrations increase
with ascorbate administration and that ascorbate effectively
functions as a pro-oxidant, rather than an antioxidant.
Preliminary evidence further suggests that the down-
regulation of manganese superoxide dismutase, a somatic
genetic alteration that occurs in castration-resistant prostate
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cancer [16], and an increase in ROS are involved in the in-
duction of molecular features of prostate cancer resistance
to hormonal therapy, through the activation of the androgen
receptor [17]. Moreover, ROS-mediated androgen receptor
activation is largely reversible upon treatment with NAC
[17]. Germline genetic polymorphisms may also play a role
in increasing ROS levels and driving tumor signaling.
Breast cancer patients with homozygous missense variants
of NAD(P)H:quinine oxidoreductase 1, which leads to ele-
vation of ROS levels, had a shorter survival time from di-
agnosis and from the time of metastasis in two independent
patient cohorts [18]. This suggests that tumors with in-
creased ROS may lead to decreased survival.
What should be concluded thus far from these intriguing
recent studies? First, the effects of ROS on tumor cells ex-
tend beyond their role in DNA damage and in promoting
early tumorigenesis. Similarly, a potential role for neutral-
izers of ROS may exist beyond prevention, after the tumor
is already established. Second, although ROS may modify
cellular signaling that is critical to driving tumor biology,
the effects of ROS are pleiotropic and nonspecific [13].
Third, the lack of effect of ROS neutralizers seen with well-
conducted randomized studies may be a result of inade-
quate concentrations [2– 4]. Fourth, a keener understanding
of how the manipulation of ROS levels affects cell signal-
ing is critical to developing a potential role for the manip-
ulation of ROS in cancer therapy. The explosion of signal
transduction modifiers in oncology over the past 10 –15
years has come mainly in the form of small molecule ty-
rosine kinase inhibitors and antibodies targeting cell sur-
face receptors, or their respective ligands. Drugs that reduce
or otherwise manipulate ROS may be used as signal trans-
duction modifiers alone or in combination with other signal
transduction inhibitors.
Although it is premature to use antioxidants for cancer
therapy, the emerging evidence suggesting that these agents
Sharifi
may reverse tumor signaling in preclinical models, along
with evidence suggesting that earlier trials of antioxidants
did not achieve biologically active concentrations, begs a
re-evaluation. Clearly, the current evidence from clinical
trials for antioxidants in cancer, including several well-
conducted and recently completed studies, is overwhelm-
ingly negative [8, 19 –21]. Clinical studies of antioxidants
that characterize the pharmacokinetics of these compounds
that also include biomarkers to validate effects on tumor-
specific signaling are required [9, 10]. Antioxidants given
in a dose and schedule that effectively decrease ROS-me-
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215
diated signaling should be tested in combination with tar-
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assessment of antioxidants for cancer given these recent
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tential role for therapy.
ACKNOWLEDGMENTS
The author has received grant support from the Prostate
Cancer Foundation. I thank Dr. Barnett Kramer for critical
review of this manuscript and for helpful comments.
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 Commentary: Antioxidants for Cancer: New Tricks for an Old Dog?
Nima Sharifi
Oncologist 2009;14;213-215; originally published online Mar 5, 2009;
DOI: 10.1634/theoncologist.2008-0219
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