Oncologist

The

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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 reactive oxygen species (ROS) in oncology is that these species 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 antioxidants. This emerging evidence on the molecular effects of antioxidants on tumor cells, along with the evidence that the route of administration of antioxidants 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 Oncologist 2009;14:213–215

Over two decades ago, reports of a role for the utility of ascorbate for use in cancer [1] were effectively dismissed with the completion of two double-blind, placebo-controlled clinical trials of oral ascorbate that showed no effect on survival in patients with advanced cancer [2, 3]. However, later studies determined that the oral bioavailability with the doses used in those studies gave a much lower exposure than i.v. administration, which was done with earlier nonrandomized trials that suggested a benefit [4]. Other studies have investigated a potential role for N-acetylcysteine (NAC) with or without vitamin A for the management of lung and head and neck cancers and have also not shown efficacy [5]. However, oral administration of NAC, which was used in this study, largely undergoes first-pass metabolism and is also scarcely bioavailable [6]. It should be noted that numerous other studies have tested various anti-

oxidants in combination with other treatments, such as chemotherapy and radiation, which is beyond the scope of the discussion here [7, 8]. Recently, several preclinical studies have suggested a critical role of reactive oxygen species (ROS) for tumor signaling and growth, along with reversibility of these ROS-mediated mechanisms that is achievable with antioxidants [9 –11]. This emerging evidence raises the question of whether we should revisit the issue of a potential utility of antioxidants for cancer therapy. Free radicals or ROS have a well-established role in the initiation of cancer through effects on DNA damage that result in mutations, leading to the activation of oncogenes and loss of tumor suppressor gene function [12]. It is in this context that ROS are typically thought of in a link to cancer and in which antioxidants have been posited to play a potential role in cancer chemoprevention. However, ROS also have

Correspondence: Nima Sharifi, M.D., Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern 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

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Antioxidants for Cancer

multiple and diverse effects on cell signaling [13]. For example, ROS play a role in the activation of the c-myc oncogene [14] and the hypoxia inducible factor (HIF)-1 transcription factor [15], which are both critical tumor signaling mechanisms that drive growth and proliferation. These and other signaling pathways may be modified by increasing or decreasing the intracellular levels of ROS. Recent 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. Although counterintuitive, hypoxia increases, rather than decreases, ROS, which are mechanistically required for the inactivation of prolyl hydroxylases, leading to the stabilization, accumulation, and activation of HIF-1 [15]. Hypoxiainduced 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 tumorigenesis 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 induce 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 hypoxic stimulation of ROS, ROS generation also occurs through other mechanisms and that ROS is involved in regulating 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 metastatic 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 inoculated with these cells, markedly inhibited metastatic activity. These findings demonstrate that ROS generation in cancer cells drives cell signaling that is critical to metastatic

activity and that direct targeting of ROS with antioxidants may reverse this process. A third recent study showed that the spectrum of antitumor 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 downregulation of manganese superoxide dismutase, a somatic genetic alteration that occurs in castration-resistant prostate cancer [16], and an increase in ROS are involved in the induction 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 elevation of ROS levels, had a shorter survival time from diagnosis and from the time of metastasis in two independent patient cohorts [18]. This suggests that tumors with increased 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 extend beyond their role in DNA damage and in promoting early tumorigenesis. Similarly, a potential role for neutralizers 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 wellconducted randomized studies may be a result of inadequate concentrations [2– 4]. Fourth, a keener understanding of how the manipulation of ROS levels affects cell signaling is critical to developing a potential role for the manipulation 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 tyrosine kinase inhibitors and antibodies targeting cell surface receptors, or their respective ligands. Drugs that reduce or otherwise manipulate ROS may be used as signal transduction 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

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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 wellconducted and recently completed studies, is overwhelmingly negative [8, 19 –21]. Clinical studies of antioxidants that characterize the pharmacokinetics of these compounds that also include biomarkers to validate effects on tumorspecific signaling are required [9, 10]. Antioxidants given in a dose and schedule that effectively decrease ROS-me-

diated signaling should be tested in combination with targeted agents for predicted synergy. A more careful assessment of antioxidants for cancer given these recent preclinical findings may lead to the re-evaluation of a potential 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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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. Proc Natl Acad Sci U S A 2008;105:11105–11109. 12 Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med 2002;347:1593–1603. 13 D’Autréaux B, Toledano MB. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 2007; 8:813– 824. 14 Benassi B, Fanciulli M, Fiorentino F et al. c-Myc phosphorylation is required for cellular response to oxidative stress. Mol Cell 2006;21:509 –519. 15 Semenza GL. Life with oxygen. Science 2007;318:62– 64. 16 Best CJ, Gillespie JW, Yi Y et al. Molecular alterations in primary prostate cancer after androgen ablation therapy. Clin Cancer Res 2005;11:6823– 6834. 17 Sharifi N, Hurt EM, Thomas SB et al. Effects of manganese superoxide dismutase silencing on androgen receptor function and gene regulation: implications for castration-resistant prostate cancer. Clin Cancer Res 2008; 14:6073– 6080. 18 Fagerholm R, Hofstetter B, Tommiska J et al. NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet 2008;40:844 – 853. 19 Lippman SM, Klein EA, Goodman PJ et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009;301:39 –51. 20 Gaziano JM, Glynn RJ, Christen WG et al. Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA 2009;301:52– 62. 21 Lin J, Cook NR, Albert C et al. Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. J Natl Cancer Inst 2009;101:14 –23.

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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 This information is current as of July 15, 2010
Updated Information & Services including high-resolution figures, can be found at: http://www.TheOncologist.com/cgi/content/full/14/3/213

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