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Antioxidants For Cancer
Antioxidants For Cancer
Antioxidants For Cancer
Oncologist ®
Clinical Pharmacology
Commentary: Antioxidants for Cancer: New Tricks for an Old Dog?
NIMA SHARIFI
ABSTRACT
Traditionally, the main focus of the importance of reac- fects of antioxidants on tumor cells, along with the
tive oxygen species (ROS) in oncology is that these spe- evidence that the route of administration of antioxi-
cies induce DNA damage, leading to a predisposition to dants in earlier clinical trials for cancer could not
cancer. However, it has recently been shown that ROS achieve pharmacologically effective levels, suggests that
may have an alternative activity, by modulating tumor antioxidants may serve as bona fide signal transduction
cell signaling. Moreover, tumor cell signaling mediated modifiers for cancer. A re-examination of the current
by ROS is readily reversible upon treatment with anti- evidence and further study is clearly warranted. The On-
oxidants. This emerging evidence on the molecular ef- 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
multiple and diverse effects on cell signaling [13]. For ex- activity and that direct targeting of ROS with antioxidants
ample, ROS play a role in the activation of the c-myc onco- may reverse this process.
gene [14] and the hypoxia inducible factor (HIF)-1 A third recent study showed that the spectrum of antitu-
transcription factor [15], which are both critical tumor sig- mor activity in mouse models is broad, with ascorbate
naling mechanisms that drive growth and proliferation. blunting the growth of several types of tumors, including
These and other signaling pathways may be modified by in- ovarian carcinoma, pancreatic carcinoma, and glioblastoma
creasing or decreasing the intracellular levels of ROS. Re- [11]. Importantly, the concentrations required for activity
cent evidence suggests that ROS-dependent signals are are similar to those achievable in humans treated with i.v.
required for tumor growth and that altering levels of ROS ascorbate [11]. Surprisingly, this line of investigation
with antioxidants or pro-oxidants could modulate tumor showed that hydrogen peroxide concentrations increase
growth. with ascorbate administration and that ascorbate effectively
HIF-1 activation occurs under hypoxic conditions. Al- functions as a pro-oxidant, rather than an antioxidant.
though counterintuitive, hypoxia increases, rather than de- Preliminary evidence further suggests that the down-
creases, ROS, which are mechanistically required for the regulation of manganese superoxide dismutase, a somatic
inactivation of prolyl hydroxylases, leading to the stabiliza- genetic alteration that occurs in castration-resistant prostate
may reverse tumor signaling in preclinical models, along diated signaling should be tested in combination with tar-
with evidence suggesting that earlier trials of antioxidants geted agents for predicted synergy. A more careful
did not achieve biologically active concentrations, begs a assessment of antioxidants for cancer given these recent
re-evaluation. Clearly, the current evidence from clinical preclinical findings may lead to the re-evaluation of a po-
trials for antioxidants in cancer, including several well- tential role for therapy.
conducted and recently completed studies, is overwhelm-
ingly negative [8, 19 –21]. Clinical studies of antioxidants
that characterize the pharmacokinetics of these compounds ACKNOWLEDGMENTS
that also include biomarkers to validate effects on tumor- The author has received grant support from the Prostate
specific signaling are required [9, 10]. Antioxidants given Cancer Foundation. I thank Dr. Barnett Kramer for critical
in a dose and schedule that effectively decrease ROS-me- review of this manuscript and for helpful comments.
REFERENCES 11 Chen Q, Espey MG, Sun AY et al. Pharmacologic doses of ascorbate act as
a prooxidant and decrease growth of aggressive tumor xenografts in mice.
1 Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment
Proc Natl Acad Sci U S A 2008;105:11105–11109.
www.TheOncologist.com
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
This information is current as of July 15, 2010