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Review

Paradoxical action of reactive oxygen species in creation andtherapy of cancer

Sina Kardeh a, Soheil Ashkani-Esfahani a, Ali Mohammad Alizadeh b,nQ1

a Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iranb Cancer Research Center, Cancer Institute of Iran, Imam Khomeini Hospital, Tehran University of Medical Science, Keshavarz Blvd.,P.O. 1419733141, Tehran, Iran

a r t i c l e i n f o

Article history:Received 28 December 2013Received in revised form4 April 2014Accepted 9 April 2014

Keywords:Reactive oxygen speciesCancerAntioxidantsReview

a b s t r a c t

A great number of comprehensive literature believe that reactive oxygen species (ROS) and theirproducts play a significant role in cell homeostasis maintenance, tissue protection against further insultsby controlling cells proliferation through inducing apoptosis, and defending against cancer. ROS isbelieved to be like a potential double-edged sword in both cancer progression and prevention. Althoughat low and moderate levels ROS affect some of the most essential mechanisms of cell survival such asproliferation, angiogenesis and tumor invasion, at higher levels these agents can expose cells to detri-mental consequences of oxidative stress including DNA damage and apoptosis that result in therapeuticeffects on cancer. Understanding the new aspects on molecular mechanisms and signaling path-ways modulating creation and therapy of cancers by ROS is critical in development of therapeuticstrategies for patients suffering from cancer. This paper presents a general overview and rationale ofparadoxical action of ROS in creation and therapy of cancer, tests to be used, and examples of how it maybe applied.

& 2014 Published by Elsevier B.V.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22. Reactive oxygen species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23. Controversy of free radical hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24. ROS sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35. Lipid peroxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46. ROS and carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

6.1. Oxidant stress and inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.2. Influence of ROS on the cell cycle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56.3. Angiogenesis induced by ROS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66.4. ROS and tumor cell invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76.5. ROS adaptation by cancer cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

7. Oxidative therapy against cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97.1. Cell death by ROS increment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97.2. ROS-induced autophagy and cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

8. Approaches to generate ROS as cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118.1. ROS-generating drugs as chemotherapeutics in cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118.2. Radiation induced-ROS as cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

9. Targeting mitochondrial ROS as cancer therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1210. Antioxidants in oxidative therapy against cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1311. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Declaration of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

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Contents lists available at ScienceDirect

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European Journal of Pharmacology

http://dx.doi.org/10.1016/j.ejphar.2014.04.0230014-2999/& 2014 Published by Elsevier B.V.

n Corresponding author. Tel./fax: þ98 21 61192501.E-mail address: [email protected] (A.M. Alizadeh).

Please cite this article as: Kardeh, S., et al., Paradoxical action of reactive oxygen species in creation and therapy of cancer. Eur JPharmacol (2014), http://dx.doi.org/10.1016/j.ejphar.2014.04.023i

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Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

1. Introduction

Cancer, medically termed as malignant neoplasm, includes awide spectrum of over 100 types of different diseases that canafflict humans with various etiologies and epidemiological dis-tributions. The eruption of this condition is initiated by uncontrol-lable reproduction of cells in a specific part of the body and alsofailure in the mechanisms of cell death. Malignant tumors, formedby rapid division of cancerous cells, can invade and destroysurrounding tissues and organs. Spreading of cancerous tumorsto distant parts of the body through the lymphatic system orbQ2 loodstream is known as metastasis (Michael et al., 2009). Canceris a major public health problem in the United States and manyother parts of the world, with regard to the fact that it isresponsible for a mortality of 1 in 4 deaths in US; the disease isranked as the second cause of deathQ3 after cardiac health problems(Rebecca Siegel and Ahmedin, 2012).

Most risk factors associated with cancer interact with cellsthrough the generation of oxidative stress. This is a condition inwhich reactive oxygen species (ROS) and/or free radicals, namelysuperoxide (O2

� ), hydroperoxyl radical (HO2� ), and hydroxyl

radical (OH�), are produced intra- or extra-cellularly, and inducetoxic impacts on cells. Oxidative stress can play an importantrole in the pathogenesis or treatment of cancer diseases. A greatnumber of comprehensive literature believe that ROS and theirproducts are responsible for important signaling functions, andplay a significant role in cell homeostasis maintenance, tissueprotection against further insults by developing preconditioning,gene transcription regulation, controlling cell proliferation byinducing apoptosis, and defending against cancer (Becker, 2004;Martin and Barrett, 2002; Nakashima et al., 2003). Under physio-logic conditions, cells control ROS levels by the use of scavengingsystems that balance ROS generation and elimination. But underoxidative stress conditions, excessive ROS can damage cellularproteins, lipids, and DNA, leading to fatal damages to cell that maycontribute to carcinogenesis (Fausto, 2006).

2. Reactive oxygen species

ROS, as byproducts of oxygen metabolism, are constantly pro-duced in the human body and removed by antioxidant defense. Highchemical reactivity is a prominent characteristic of these chemicalagents; therefore, these factors are believed to be toxic in cellularlife (Auten and Davis, 2009). Given the higher stability of pairedelectrons positioned in an orbital compared to single electrons, it isexpected that radicals express a higher degree of reactivity thanQ4 non-radicals (Halliwell, 1991a). The interest to radical agents rose in 1970safter the discovery of superoxide dismutase (SOD) in 1968. Removalof superoxide radicals, a species with an extra electron than theoxygen molecule, is enhancedQ5 by SOD enzymes (Ebrahimi et al.,2012; Jouroukhin and Gozes I, 2012). Although ROS play a positiverole in normal physiological pathways and necessary functions, theirexcess concentrations and overproduction are immensely toxic tocellular life by damaging macromolecules such as DNA and proteins.This potential toxicity is magnified in the presence of transitionmetal-ions such as iron oQ6 r copper (Aruoma and Halliwell, 1991).Briefly, along with the traditionally known damaging impact oncells, ROS are also considered as modulators of pathologic processes.ROS functioning on both sides of death and life, physiological and

pathological processes has made some paradoxical view on theiractions (Thannickal, 2003). Among these features, mediation ofphenotypes in endothelial cell and smooth muscles, such as growth,apoptosis and survival can be mentioned (Fay et al., 2006). However,the determining factor of final response to ROS is mainly theintracellular target, which is dependent on other influential factorssuch as type of oxidant, kin Q7etics and quantities of chemicals involved(Zhou et al., 2013). It is suggested that the key explanation ofparadoxical ROS actions may lie in reversible oxidation–reductionreactions mediated by ROS also called as redox signaling (D’Autréauxand Toledano, 2007). ROS modulate the signaling of growth factors,G-protein-coupled (GPC) receptors, Wnt, and Notch and also itsdownstream cascades including the Janus kinase and signal transdu-cer and activator of transcription (JAK–STAT), mitogen-activatedprotein kinase (MAPK), Nuclear factor-kappaB (NF-κB), and phospha-tidylinositol-3-kinase/protein kinase b (PI3K/AKT) (Finkel, 2000).Key transduction pathways are mediated by reversible oxidation ofcertain components of signaling through ROS. High chemical reac-tivity is a prominent characteristic of ROS, which can be classifiedinto two groups of free radicals, including O2

� , peroxynitrate(ONOO�), and OH� , and also non-radicals such as ozone (O3),hydrogen peroxide (H2O2), and hypochlorous acid (HClO) (Berlettand Stadtman, 1997). The previously mentioned damage of ROS tobiomolecules is mediated by free radical chain reactions. Variousstimuli, including growth factors, chemotactic factors, cytokines,hypoxia, and shear stress can give rise to production of ROS as aresponse. Transcription factors such as hypoxia-inducible factor1-alpha (HIF1-α), activator protein 1 (AP-1), and NF-κB can them-selves be directly modified in a redox-sensitive manner, therebyleading to an altered transcriptional profile of gene products(Michiels et al., 2002). Remarkably, subcellular regions may spatiallyconfine the redox signaling. Specificity of ROS in gene regulation andcellular functions and their participation in dynamic cell functionssuch as cell migration that represents the synchronization ofdifferent and distant parts of the cell are ensured by the classificationof redox signaling (Irani, 2000). Among these reactions, attack toDNA bases, abstraction of hydrogen atom from molecules such asthiols, and also activation of lipid peroxidation, in which fatty acidchain of phospholipids in membrane are targeted, can be named(Halliwell, 1991b). Although ROS are not known as the first rankcause in most diseases, targeting of these molecules based on acrystal clear understanding of their generation and involvement incellular mechanisms can enhance the therapeutic course by delayingthe initial signs of break out and also lessening the stage severity ofdisease.

3. Controversy of free radical hypothesis

Although ROS was first implicated as deleterious and destruc-tive in events such as ischemia reperfusion (IR) injury, laterfindings revealed that these agents could also be implicated inthe processes involved in maintenance of homeostasis (Becker,2004; Feinendegen, 2002). They can play an important rolein preventing diseases through supporting the immune system,intervening in cell signaling and mediating apoptosis. On the otherhand, they can also be responsible for carcinogenesis and cardio-vascular diseases by damaging valuable macromolecules in cells(Alizadeh et al., 2012; Alizadeh and Mirzabeglo, 2013; Faghihiet al., 2012; Finkel and Holbrook, 2000b; Holbrook and Ikeyama,

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2002). Recent evidence emphasized that ROS production is sovital in normal physiological process, especially for appropriateimmuno-competence and activation of several signal transductionpathways (Holbrook and Ikeyama, 2002). There are several studiesreporting unsuccessful results in applying antioxidants in order torestore the function of tissues suffering from pathologies in whichROS play the most important role (Domijan et al., 2014; Sheu et al.,2006). Some other studies described diverse side effects arisingfrom antioxidant administration as well, which is opposed to theanticipated effects of these substances (Horakova et al., 1992).Some epidemiological studies supporting this idea, demonstratedthat ischemic heart disease and specific types of cancer wereinversely related to the endogenous antioxidant condition (Geyet al., 1991). Other investigations also indicated that antioxidanttherapy might even be deleterious in conditions such as lungcancer or cardiovascular diseases (Omenn et al., 1996). Armarioand his colleagues showed that despite inhibition of lipid perox-idation in the gastric mucosa by vitamin E or allopurinol,ischemia-reperfusion-induced lesions were not decreased at all(Armario et al., 1990). Many studies believed that excessive ROSproduction is a consequence of tissue injury rather than the causeof damage itself. It has been indicated that the peak of hydroxylradical concentration did not match with cell injuries (Khalidand Ashraf, 1993). There are also disappointing clinical evidence

indicating the failure of antioxidant supplementation for oxidativestress-associated pathologies such as cancer, cardiovascular dis-eases, coronary artery diseases, Alzheimer's disease, and chronicobstructive pulmonary disease (COPD) (Gilgun-Sherki et al., 2003;Lonn et al., 2005; Tousoulis et al., 2005; Vivekananthan et al.,2003). The idea of antioxidants therapy has some controversiesand the ideal antioxidant strategy is still unidentified. We believethat with regard to different pathophysiology of diseases in whichROS are involved, selection of the exact antioxidants and methodsof introduction to body directly affects the success or failure in thefinal results. On the other hand, the local life style of patients maybe the underlying interfering factor responsible for controversialresults of cohort studies with same method. Furthermore, despitethe difficulties in measuring the bioavailability of tissue antiox-idants in targeted organs, this may clear the conventional para-doxical notions about antioxidant therapy if done with standardcriteria in large studies.

4. ROS sources

Mitochondrion is perhaps the most important in vivo sourceof ROS (Fig. 1). The mitochondrial electron transport chain (ETC)has several redox centers, which may leak electrons to molecular

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oxygen, serving as the primary producer of ROS in most of thetissues (Ott et al., 2007). Mitochondrial ETC generates primary ROSat two complexes, I and III. HO2

� and O2� radicals are produced

from ROS in a number of cellular reactions and by differentenzymes, e.g., lipo-oxygenase (LOX), nicotinamide adenine dinu-cleotide phosphate (NADPH) oxidase, xanthine oxidase (XO), SOD,and peroxidase (Blokhina et al., 2003; Finkel and Holbrook,2000a). Lipids, by peroxidation of unsaturated fatty acids in themembranes are the main cellular components which are suscep-tible to damage by free radicals (Blokhina et al., 2003; Saki et al.,2013).

XO is a major source of O2� which can generate HO2

� as well.This enzyme is present in endothelial cells and at higher levels inblood circulation. The interactions of neutrophils and endothelialcells play an important role directly in ROS production throughconverting the enzyme, xanthine dehydrogenase (XD), into XO. Ithas been discovered that XO is placed in coronary endothelial cellsbut cannot be found in the human cardiac myocytes (Guntheret al., 1999).

Cytochrome P450 enzymes are other potent sources of ROSproduction, particularly in the liver. These are a group ofmembrane-bound enzymes named the cytochrome mixed func-tion oxidases, mostly present in the endoplasmic reticulum asconstituents of a multi-enzyme system. This system comprises theflavin adenine dinucleotide/flavin mononucleotide (FAD/FMN)-including NADPH-P450 reductase and cytochrome b5. Althoughmost of them are localized in the endoplasmic reticulum, they aremainly found in the mitochondria (Anandatheerthavarada et al.,1999; Ortiz de Montellano, 1995).

Recent evidences suggested that peroxisomes have a significantpart in both the production and scavenging of ROS in the cell,especially hydrogen peroxide (H2O2) (Stolz et al., 2002; Zwackaet al., 1994). An appealing characteristic of peroxisomes is theircapacity to reproduce and multiply, or be degraded as a reaction tonutritional and environmental changes. The existence of a numberof H2O2 producing oxidases along with catalases in peroxisomes isan important indicator demonstrating the contribution of peroxi-somes in the metabolism of oxygen metabolites (Okuno et al.,2009; Stolz et al., 2002; Tower et al., 2011; Zwacka et al., 1994).In addition, large quantity of ROS such as O2

� , H2O2 and theirderivatives are made by activated macrophages and neutrophilsthrough the phagocyte isoform of NADPH oxidase (Nox) or what iscalled respiratory burst oxidase (Babior, 1999). The phagocytic Noxhas a significant role in host defenses against microbial attacks viaproduction of superoxide anions (Babior, 1984) and other ROSfor example hypochlorous acid (HClO), the most potent physiolo-gical oxidant and antimicrobial agent which is generated throughcombined reactions of Nox and myeloperoxidase (MPO) (Hamptonet al., 1998). The considerable effect of this function in humanis exhibited by a genetic disorder called chronic granulomatousdisease mostly presenting with severe bacterial and fungalinfections. This deficiency is due to an absence of one of thecomponents of the NADPH oxidase leading to shortage of ROS(Kannengiesser et al., 2008; Roos et al., 1996). Lastly, detection ofthe exact sources of ROS production is the ultimate key to theevolution process of making drugs that can increase or inhibitoxidative stress though very specific pathways and thus targetingonly certain cell lines.

5. Lipid peroxidation

Lipid peroxidation is the oxidative process of lipid degradationby ROS that are either by products of cellular metabolic reactionsor oxidativQ8 e stress (Marnet, 2002; Young and McEneny, 2001).Uncontrolled reaction of ROS with the present membrane lipids,

especially polyunsaturated fatty acid chains, will lead to a myriadgeneration of free radicals produced in chain reaction that rendersdeterioration of the membranes (Feeney and Berman, 1976). Theprocess consists of three chief steps in resemblance to all free-radical chain reactions: Initiation, Propagation, and Termination(Fig. 2) (Marnett, 1999). In the initiation phase of the peroxidationchain reaction, a ROS molecule reacts with an unsaturated fattyacid chain. The products of the initiation step are a fatty-acidradical and a humble water molecule (Dix and Aikens, 1993). Sincethe fatty-acid radical is not a stable molecule, in the propagationphase, it tends to react with molecular oxygen (O2) to produce alipid-proxyl radical. This generated molecule then reacts with yetanother unsaturated fatty acid and produces another fatty-acidradical in addition to a lipid peroxide. The fatty-acid radical takespart in another cycle of the same series of reactions and producesmore free radicals and lipid peroxides in a continuous chainreaction. This step is responsible for the vast deterioration ofcellular membranes induced by ROS during oxidative stress(Svingen et al., 1979; Young and McEneny, 2001). Like other free-radical chain reactions, the cycle only terminates when a freeradical reacts with another free radical to produce two neutralmolecules. In the absence of antioxidants, such reaction happenswhen the membranes have undergone a great deal of damage,resulting in high concentrations of free radicals and increasing thechance for interaction between two free radicals (Yin et al., 2011).If the lipid peroxidation process is not terminated in a shortperiod, considerable measures of oxidative damage are dealt tothe cell membrane (Yajima et al., 2009). Moreover, products oflipid peroxidation process, such as malondialdehyde, are proved tobe carcinogenic and mutagenic since they can deteriorate the DNA(Niedernhofer et al., 2003). Also, targeting lipid peroxidation is acharacteristic of some virulent invaders. Oxidatively damaged DNAand lipid have been detected in HCV core-protein-transgenicmice while presenting robust accumulation of ROS (Machidaet al., 2006). In an evolutionary cycle to control lipid peroxidationorganisms have developed defense systems such as antioxidantsto terminate the chain reaction before it can damage the mem-branes. Certain vitamins (e.g., Vitamin E) and enzymes such asglycogen phosphorylase, SOD and Catalase play a major role inearly termination of lipid peroxidation chain reaction (Huanget al., 2002; Zimmermann et al., 1973).

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Fig. 2. The process of Lipoprotein peroxidation consists of three steps: Initiation,Propagation, and Termination. The two former steps are depicted (Picture kindlyprovided by Tim Vickers off copyrights).






6. ROS and carcinogenesis

6.1. Oxidant stress and inflammation

Inflammation is classified into two major stages: acute andchronic. As the initial stage, acute inflammation is mostly due tothe “respiratory burst” caused by mast cells and leukocytes as aresponse against an exogenous invasion (Reuter et al., 2010). How-ever, in the chronic stage the increased release of mediators such asmetabolites of arachidonic acid, cytokines, and chemokines byinflammatory cells recruit inflammatory cells to the site of damagewhich will ultimately result in a higher level of ROS production andpredispose the host to various chronic illnesses, including cancer(Grivennikov et al., 2010; Kamp et al., 2011). The more this viciouscycle of sustained inflammation and oxidative stress persists, thehigher the risk of carcinogenesis will be (Shacter and Weitzman,2002). As an example of the synchronous development of cancer andinflammation progression, interleukin (IL)-1 and IL-6 proinflamma-tory cytokines can be induced by various malignant cells with ratsarcoma (Ras) oncogene (Bhaumik et al., 2009). On the other side ofthe cycle, certain antioxidants and steroids that have the ability toinhibit the phagocyte respiratory burst can regress tumor promotion(Fabiani et al., 2001). Besides contributing to genomic instability, ROScan specifically trigger certain pathways involved in tumor prolifera-tion (Weinberg et al., 2010). For example, as an episode of inflamma-tion induced carcinogenesis, nitrosative stress can activate AP-1, aredox-sensitive transcription factor, which promotes cell divisionand transformation (Matthews et al., 2007; Schonthaler et al., 2011).Although NO� is a short lived free radical, the expression of theinducible nitric oxide synthase isoform (iNOS) by inflammatorycytokines such as tumor necrosis factor (TNF)-α and interferon-γcan produce deleterious damages (Tyagi et al., 2012). The up-regulation and the activity of iNOS has been associated to tumorangiogenesis in human colorectal cancer (Cianchi et al., 2003;Gochman et al., 2012). Matrix metalloproteinase (MMP)-2 and -9, asubgroup of MMPs which play critical role in collagen degradationand tumor invasion, are activated under prolonged oxidative stressand inflammation (Gencer et al., 2013). Redox signaling of a numberof metastatic cascade steps are also regulated by the inflammatorymolecule electrophilic cyclopentenone prostaglandin (Diers et al.,2010). Studies have indicated that ROS are involved in the releaseof vascular endothelial growth factor (VEGF) and fibroblastgrowth factor (FGF) into tumor environment by inflammatory cells(Blanchetot and Boonstra, 2008). Hence, it can be concluded thatcarcinogenesis can be affected by both the oxidative stress and ROSinduced inflammation (Fig. 3). There is also a probability that patientswho are presenting a chronic higher level of inflammation andoxidative stress in minor conditions e.g., skin conditions such asacne and psoriasis (Pouplard et al., 2013; Sutcliffe et al., 2007) aremore prone to develop cancers in elderly in comparison to normalindividuals. Therefore, controlling inflammation in such patients mayprevent future risks.

Several of the inflammatory cells including mast cells, macro-phages, eosinophils, and neutrophils which are believed to parti-cipate in the inflammatory response have been shown to releaseROS after activation by a variety of stimuli (Gillissen et al., 1997;Reid et al., 2003). Superoxide dismutase plays an importantrole in conversion of O2, produced by inflammatory cells, toH2O2 (Shuvaev et al., 2011). HOCL, a potent oxidant, is formedin neutrophils myeloperoxidase from H2O2 and chloride ions(Eiserich et al., 1998). O2 can also be released from eosinophils inresponse to different allergenic or parasitic related factors such ascomplement fragments, IgG, IgE, platelet-activating factor (PAF)and the lipid mediator (Dri et al., 1991). Interaction of eosinophilproducts including cationic proteins, eosinophil peroxidase (EPO)and major basic protein are correlated to epithelial damage; EPO

and hydrogen peroxide are two arms of a cytotoxic system in thepresence of halide ions. This phenomenon is vastly studied inasthma attack in which blood vessels containing purified amountsof PAF activated eosinophil granulocytes directly rushes to airwayepithelial cells. The initiation of the attack may be linked toarachidonic derived chematactic factors stimulated by increasedlevels of ROS (Wenzel, 1997). As a noticeable reduction of in vitrodamage is observed after applying of catlase, it is suggested thatthe reaction is mostly mediated by ROS (Barnes, 1990). Nasalepithelium is also exposed to this injurious effect of H2O2 and EPO(Holm et al., 1999). In late phases of allergen exposure ROS maycontribute to attraction of macrophages and also mucus hyperse-cretion (Barnes, 1990). While blood histamine and vessel diameterrises in a high ROS cellular context, it is therefore much morereasonable that ozone inhalation will ultimately lead to infiltrationof neutrophils (Schierhorn et al., 1999). Lacroix et al. study on theinjured spinal cord demonstrated that delivery of interleukin 6(IL6) can increase neutrophil and macrophage infiltration which inturn inhibits axonal growth (Lacroix et al., 2002). Studies provedthat IL6 is a modulator of both ROS generation and neutrophiltrafficking (Fielding et al., 2008; Sung et al., 2000). Assays of celldetachment and digestion of cell surface proteins in excessiveneutrophil mediated inflammatory reaction are an index of anoi-kis, a special form of cell death promoted by disconnection ofanchorage-dependent cells from extracellular matrix (ECM) (Liet al., 1999). A direct relationship between intracellular ROS andcell detachment coincided by a burst in number of inflammatorycells describes the significant role of neutrophils in inductionof tissue damage (Harlan et al., 1981; Rafiq et al., 2006).Ischemia-reperfusion injury of tissues characterized by microvas-cular impairment and enhanced leukocyte infiltration is frequentlyassociated with formation of ROS (Grisham and Granger, 1988).in vivo studies represent that the reperfusion of ischemic tissueswhich is concomitant with release of leukocyte generated ROS,mainly inflammatory cells NADPH oxidase, may result in substan-tial damage of different tissues including epithelial cells of inter-stitial mucosa and hepatic mesenchymal cell structure (Jaeschkeet al., 1990; Simpson et al., 1993).

6.2. Influence of ROS on the cell cycle

A broad range of external cellular factors including growthfactors and extracellular matrix factors are known which takepivotal parts in regulating the cell cycle. Cyclins and cyclindependent kinases (CDKs) are two classes of molecules with majorimpact on cell cycle. On the upper level cell division cycle (Cdc)-25phosphatases and CDK-inhibitors (CKIs) control the activity rate ofcyclins and CDKs by reversible phosphorylation. Recent researcheshave shed light on the synchronous production of ROS with thenormal cell cycle and their key role as a vital modulator (Takahashiet al., 2004). It has become clear that the ROS produced down-stream of growth factor receptors induce ubiquitination by inter-mediate phosphorylation of CDKs and other regulatory factorssuch as epidermal growth factor receptor (EGFR) (Colavitti et al.,2002). In addition, activation of EGFR results in increased tran-scription and translation of molecules in intracellular signalingpathways involving cyclins and CDKs and also escalated ROScontent which proves a synergistic correlation of the mentionedagents. Despite the studies that have clarified the role of ROS asa positive progression factor in cell cycle process, conspicuousresults of recent studies assert that generation of ROS fromdifferent sources may have contrasting consequences in adjustingthe cell cycle and the related enzymatic systems, considerably theCdc-25 (Boonstra and Post, 2004). Apparently, the exact effectsof ROS on both phosphorylation and ubiquitination dependson cellular and molecular context including the amount and the

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specific types of ROS produced and also cell cycle associatedenzymes (Verbon et al., 2012). Feher et al. have provided evidentdata of positive effects of oxidative stress and ROS on theacceleration of Auxin-mediated G0-to-G1 phase in plant cell cyclemechanism (Fehér et al., 2008). A study of the outcomes ofoxidative stress on neurodegenerative disorders by Klein et al.affirmed both cell cycle and ROS as team players in progression ofthe disease, and concluded that cell cycle in neurons can berepressed by ROS (Klein and Ackerman, 2003). In summary, it isapparent that ROS may play an important role in activation ofgrowth factor receptors, and thus modulate cell cycle progressionin cancer (Fig. 4). Considering the reactions of different tumor celllines for survival, studies on behavior of cancers in response tochanges in ROS level and arrested proliferation are required toreveal weather halted cell cycle may affect other factors such astumoral invasion and metastasis in long terms.

6.3. Angiogenesis induced by ROS

Inadequacy in oxygen supply to cells by prolonged hypoxialeads to cell death. As new blood vessels are atypical or the blood

flow is poor, tumors often turn to be hypoxic. Under this condition,cells upregulate signaling pathways which activate proliferationand angiogenesis. These pathways have been adapted in cancercells effectively which allow tumors to stay viable and grow undersuch conditions (Harris, 2002). The reperfusion of hypoxic tissuecan rise the free oxygen radical levels (Prabhakar, 2001). ROSproduced by hypoxia/reoxygenation not only have detrimentaleffects in cells such as tissue injury, but also have an importantrole in vascular angiogenesis (Fig. 5) (Maulik and Das, 2002).

Angiogenesis is essential for both physiological processes likeembryonic development and wound healing and pathologicalchanges such as cancer, diabetic retinopathy, and atherosclerosis(Maulik and Das, 2002; Tonnesen et al., 2000). Necessary events inthe process of angiogenesis include endothelial cell migration,proliferation, and tube formation. ROS may directly play a part inall these events, as H2O2 has been indicated to be involved inproliferation and migration of endothelial cells and to mediatelymphocyte-activated tubulogenesis (Fig. 5) (Maulik and Das,2002; Soares et al., 2014). Furthermore, low concentrations ofsuperoxide was shown to accelerate endothelial cell migration andtube formation in an in vitro model of angiogenesis (Stone and

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Fig. 3. The interrelationship between inflammation induced ROS and pathways of cancer promotion.






Collins, 2002). ROS also act as mediators of angiogenic growthfactors, such as VEGF (Kuroki et al., 1996). It has been demon-strated that NADPH oxidase not only induces the expressionof VEGF (Arbiser et al., 2002) but also regulates VEGF-inducedangiogenesiQ9 s (Ushio-Fukai et al., 2002a, 2002b). Previous studiesalso revealed that ROS can enhance the production of angiogenicfactors such as IL-8 and VEGF. Besides, ROS elevate the secretion ofthe MMP-1 by tumor cells leading to neovascularization withinthe tumor microenvironment (Brown et al., 2000; Milligan et al.,1996).

Another mechanism by which oxidative stress affect the bloodsupply within the tumor is by triggering vasodilatation. ROS

activated heme oxygenase-1, results in production of carbonmonoxide, or induces iNOS leading to nitric oxide (NO) produc-tion. Both carbon monoxide and nitric oxide are vasodilators(Milligan et al., 1996). It is also worth knowing that ROS mayincrease the risk of tumor metastasis by promoting vascularpermeability, either by direct endothelial cell injury or by theup-regulation of iNOS or heme oxygenase-1 (Brown and Bicknell,2001). It has been reported that the activity of the ROS-generatingenzyme Nox1 is essential for up-regulation of VEGF, a powerfulstimulator of tumor angiogenesis (Komatsu et al., 2008) and alsoVEGF receptors such as VEGF-R1 and VEGF-R2 are considerablyinduced in vascular cells in Nox1-expressing tumors. Nox1 is apotent activator of the angiogenic switch, elevating the tumorvascularity and regulating molecular markers of angiogenesis.Matrix metalloproteinase activity, another indicator of the angio-genic switch, also is stimulated by Nox1. Recent evidence reportedthat Nox1 induction of VEGF is reduced by co-expression ofcatalase, showing that hydrogen peroxide signals take part in theangiogenic switch pathway (Arbiser et al., 2002).

It has been investigated that free radicals can increase levelsof HIF-1, a transcription factor responsible for cell adaptation tohypoxia and in charge of the oxygen-dependent expression ofVEGF gene (Chandel et al., 1998), implying that oxidative stress incarcinoma cells might cause increased HIF-1 induction duringhypoxia condition leading to further production of VEGF (Chandelet al., 2000; Richard et al., 2000). As a final point, ROS productionis a consequence of cell exposure to alternate hypoxia–reoxygena-tion condition which per se represents a potent pro-angiogenicstimulus.

6.4. ROS and tumor cell invasion

Cell migration and invasion of tumor cells are the inceptivedeterminant elements in metastasis and prognosis of cancer.Through a complex multistep process and a series of cellularevents involving cytoskeletal changes which result in attachmentof tumor cells to the basement membrane, degradation of theextracellular matrix and migration through the degraded stroma,cells detach from the initial tumor location and metastasize toremote areas (Liotta and Stetler-Stevenson, 1990). Stimulationof cell surface receptors or amplification of intracellular signalstriggers signaling pathways that maintain and provoke thesechanges. ROS are classified among the factors that participate in

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101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566 Fig. 5. Hypoxia/Reperfusion induction of ROS and involvement of mediators in neovascularization and angiogenesis.

Fig. 4. Mediators involved in ROS regulation of cell cycle.






tumor cytoskeletal dynamics and invasion (Fig. 6) (Friedl andAlexander, 2011). It has been suggested that various pathways inthe family of MAPK are activated in consequence to stimulationof receptor tyrosine kinases (RTKs) by ROS during cell migration(Hurd et al., 2012). In response to elevation of growth factorcontent and thus stimulation of the related receptors such asplatelet derived growth factor (PDGF) and VEGF, the rise in thelevels of the specific types of generated ROS leads to enhanced cellmigration (Ushio-Fukai et al., 2002a, 2002b). Cellular protrusionsare the initial steps in alteration of actin cytoskeleton and promo-tion of cell migration. As a downstream production of differentsignaling molecules that contribute to dynamicity of cytoskeleton,ROS are considered as both direct and indirect agents affecting cellmigration. For example, an increase in Rac 1 induction of actinpolymerization is significantly correlated to heightened levels ofavailable superoxide (Moldovan et al., 1999). ROS are known tohave superior control via stimulation slingshot (SSH) proteins onthe activity of cofilin, an agent that can regulate actin remodelingand de-polymerization by modulating the formation of lamellipo-dia which are a leading class of actin rich protrusions in cellmigration (Kim et al., 2009). Studies report that prior to tumor cellmigration, localization of high amounts of cofilin to lamellipodiacan help tumor cell migration (Friedl and Gilmour, 2009; Lai et al.,2008). Apart from lamellipodia formation, neurites and F-actin arealso other cellular protrusion that ROS are considered as theiressential regulating factors (Munnamalai and Suter, 2009). Migra-tion of tumor cells is followed by cellular adhesion process whereintegrins are proven to be central modulators by formation of focaladhesion, a connection between extracellular matrix (ECM) andtumor cell cytoskeleton (Svineng et al., 2008). Integrin signaling isaccompanied by phosphorylation of focal adhesion kinase (FAK),Paxillin and p130Cas, which is mediated thorough oxidative burstand ROS generation from multifarious sources notably Nox, mito-chondria and lipoxygenases (Gozin et al., 1998; Taddei et al., 2007).In addition, MMPs comprise more than 26 types of zinc dependentendopeptidases with the ability to degrade ECM componentsthat have been associated to several steps of cancer cell invasion(Egeblad and Werb, 2002; Overall and López-Otín, 2002). There

are now considerable amount of documents on ROS regulatedexpression of MMPs in diverse types of cancers including pan-creatic cancer, glioblastoma and breast cancer (Ellenrieder et al.,2000; Inoue et al., 2010; Nakopoulou et al., 2003). Ma et al. (2013)explored mitochondrial respiratory defect involvement in cancerpathogenicity using Rotenone inhibitor of electron transportcomplex-I to generate breast cancer clones. In comparison toparental cells, increased ROS and higher migration were expressedin the cancerous clones. Further observations depicted antiox-idants such as polyethylene glycol (PEG)-catalase and Mito-TEMPOas potent inhibitors of tumor invasive behaviors. As an example inanimal models, expression of human catalase gene (mCAT) couldsignificantly reduce invasion of breast cancer cells in trans-genic (MMTV-PyMT) mice that develops metastatic breast cancer(Goh et al., 2011). Conspicuously, HIF-1-a and VEGF are the up-regulators of ROS (Ma et al., 2013). In a study by Alili et al. in vivomelanoma tumor invasion in immunodeficient mice was subsideddue to treatment with redox active cerium oxide nanoparticles(CNPs) (Alili et al., 2013). Luanpitpong et al. demonstrated the roleof caveolin-1 (Cav-1) as a collaborator to cancer aggressive inva-sion of human lung carcinoma H460 cells. Cav-1 is regulated byintracellular ROS; however, its expression varies depended on theinteraction of Cav-1 and different types of ROS. Hydrogen peroxideand superoxide anion inhibits cell migration by down regulation ofCav-1 while invasion is provoked by hydroxyl radical stimulationof Cav-1 (Luanpitpong et al., 2010). These results emphasizes thatROS can be controlled to prevent invasion and end stage cancer.

6.5. ROS adaptation by cancer cells

Depending on the present molecular context ROS can exerttheir heterogeneous chemical properties by regulating a widerange of downstream pathways (Fig. 7). Although at lowand moderate levels ROS affect some of the most essentialmechanisms of cell survival such as proliferation and homeostaticsignaling, at higher levels these agents can expose cells to detri-mental consequences of oxidative stress including DNA damage,gradual senescence and also apoptosis caused by mitochondrial

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Fig. 6. The process of ROS induction and up regulation of cellular invasion in cancer.






permeabilization and the release of cytochrome c (Gao et al., 2007;Giannoni et al., 2005; Nakashima et al., 2003; Ramsey andSharpless, 2006). Therefore, in an attempt to counteract thesedeleterious aftermaths of ROS overload which may unstable thecell viability, stressed cells trigger a variety of adaptation mechan-isms by utilizing redox buffering systems and antioxidants(Fruehauf and Meyskens, 2007). Reduced glutathione (GSH) andthioredoxin (TRX) are two NADPH dependent antioxidants thatrestrain ROS cytotoxic effects and prevent the possible irreversibleimpairments by lowering the excessive levels of ROS. Regardingthe oncogenic mutations that increase anomalous metabolism,escalated rates of ROS are a primary component of highly pro-liferative cancer cells environment. Thus, to impede this accumu-lation of ROS and maintain a higher level of tolerance, tumor cellsinitiate vast up-regulation of multiple antioxidant systems such asSOD, catalase, and peroxidases (Sundaresan et al., 1995; Vaughnand Deshmukh, 2008). Hence, with regard to this synergeticincrease in both ROS content and antioxidants, it can be concludedthat cancer cells control oxidation state by balancing the involvedfactors at higher levels than normal cells. However, loss of tumorsuppressors in development process of cancer cells may provokeaberrant metabolism and disturb the cellular control over thestabilization of redox state. For example the deletion of TSC2tumor suppressor hyperactivates mammalian target of rapamycin(mTOR) which in turn leads to inordinate translation and produc-tion of ROS (Li et al., 2010; Ozcan et al., 2008). Similar imbalancesin regulation of the oxidation state have been observed in theabsence of other tumor suppressors such as PTEN (Nogueira et al.,2008). In a comparable theory, P53 plays an important role incellular defense against oxidative stress by mediating the tran-scription of nuclear factor-erythroid 2-related factor 2 (Nrf2) anup-regulator of several detoxifying antioxidants (Budanov et al.,2004; Liu et al., 2008, 2009). Studies have demonstrated thatDJ1 as an anti-degrading factor in neural tissues may stimulatetumorgenesis by balancing oxidative stress and preventing ROSinduced apoptosis (Kahle et al., 2009). Given that in the absence ofthese tumor suppressors additional oxidative stress may induceselective killing of malignant cells, therefore, it is hypothesizedthat these mutations can be clinically exploited by targeting tumorcells with vast amounts of ROS.

7. Oxidative therapy against cancer

Although oxidative stress, considered as the imbalance ofROS production and its clearance by antioxidant defenders, is theprimary cause of injury to cellular components and thus cell death,recent researches propose that selective induction of oxidativestress might be utilized as an advantageous factor in certain

conditions (Dawson and Kouzarides, 2012). As tumor cells aredistinguished by abnormal oxidation state and extensive amountsof ROS generation, investigating the possibility of selective target-ing of cancer by drugs that can differentiate uncontrollable tumorcells from normal cells may be an efficient method in eliminatingmalignancies (Tandon et al., 2005). Hileman et al. study results ofintracellular O2

� content and apoptosis analyses, depicted thatthe more the oxidative stress increases, the more the cancerouscells relies on antioxidant enzymes (Hileman et al., 2004). Anoverlook on the killing mechanism of mainstream treatmentmethods of cancer, including irradiation and chemotherapeuticdrugs, notified researchers that overproduction of ROS is acommon pathway in all these leading therapies. Exhausted capa-city of adaptive defenses such as SOD and other antioxidantsstroke the forerunners of cancer therapy with the idea of applyingROS generating chemicals and also antioxidant inhibitors toenhance the prognosis of patients by triggering apoptosis incancer cells (Kong et al., 2000; Kong and Lillehei, 1998). Furtherstudies conducted on ovarian cancer and human leukemia cellsdemonstrated that the stability of cancer cells can be much moreeasily disturbed thorough 2-methoxyestradiol (ME) mediated SODinhibition than normal cells (Aguilo et al., 2012; Brown et al.,2009). With regard to the most recent and available data, it isevident that targeting the oxidative stress inside the cancer byexposing the cells to further ROS can be the provoker of a newgeneration of experimental cancer therapies that can be usedalone or in combination with previous methods.

7.1. Cell death by ROS increment

ROS are believed to be like a potential double-edged sword inpreventing and slowing the progression of disease. Temporarychanges in ROS concentration in the body can affect activityof signal transduction pathways leading to either cell proliferation,or to apoptosis and necrosis, regarding to the dosage and durationof ROS and also the type of cell. Normally, low doses can bemitogenic, while medium doses of ROS cause transient or perma-nent growth arrest, and high doses usually lead to cell deathcaused by apoptosis or necrosis (Holbrook and Ikeyama, 2002).This issue becomes more notable when precise concentrationof ROS are required for normal cell function such as promotingapoptosis of precancerous or transformed cells (Martindale andHolbrook, 2002). For instance, some chemotherapy drugs andradiation therapies targeting cancer cells by producing high levelsof ROS could possibly be interfered by antioxidant supplements(Seifried et al., 2004).

Disproportionate ROS levels may harm major cellular compo-nents such as DNA, proteins, lipids and membranes. Subsequent tomitochondrial lipid and protein oxidation, permeability of themitochondrial membrane increases, and then the coupling effi-ciency of the electron transport chain is altered, leading to furtherproduction of free radicals, and the release of cytochrome c,and finally activating the apoptosis which depends on caspases(Conklin, 2004). It has been reported that the key mechanism bywhich oxidant agents may kill cells is the activation of apoptosis.More evidence showed that the oxidative stress can stimulatec-Jun N-terminal kinase (JNK) and caspases to initiate apoptoticcell death (Conde de la Rosa et al., 2006; Czaja et al., 2003) and thispathway can be attenuated through activation of protein kinase Cand extracellular-signal-regulated kinase (ERK) 1/2 leading todown-regulation of JNK (Singh and Czaja, 2007). In some cases,the high concentrations of ROS may prevent apoptosis at a caspaselevel and switch the process toward necrosis (Chandra et al.,2000). This diversion is essential in solid tumors and requiresextensive amounts of ROS, a reduction of ATP and some changes inthe mitochondrial ETC (Lee et al., 1999). Therefore, different ROS

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Fig. 7. ROS adaptation by cancer cells.






can cause necrosis via mechanisms involving mitochondrial per-meability transition pore (mPTP) opening, breakdown of themembrane potential and ATP reduction (Nieminen et al., 1997).Nonetheless, the extracellular ROS do not trigger the mPTPbut they make effects via oxidation of NADPH, Ca2þ uptake andmitochondrial ROS production (Nieminen et al., 1997). Takentogether, these results support the important pathophysiologicalrole of ROS in discrete apoptotic signaling pathways.

7.2. ROS-induced autophagy and cancer therapy

Autophagy, also called a process of ‘self-eating’, is an evolu-tionary conserved pathway and one of the nonapoptotic cell deathmechanisms (Huang and Klionsky, 2002; Klionsky, 2007), whichserves a housekeeping role and include engulfment of damaged orincorporated organelles into double membrane vesicles namedautophagosomes. It has been illustrated that autophagy partici-pates in several diseases such as cancer, infectious diseases,myopathies, and neurodegenerative disorders (Komatsu et al.,2006; Zhou and Spector, 2008). Recent evidence demonstratedthat chemotherapeutic drugs induce autophagy in different kindsof cancer cells (Table 1) (Levine and Kroemer, 2008). On one hand,autophagy plays a crucial role in cell protection that allows cells tosurvive against cytotoxic agents; on the other hand, it can lead tocell death called autophagic cell death (Kondo and Kondo, 2006;White and DiPaola, 2009). Numerous works have describedthe beginning of autophagic mechanism in response to oxidativestress. Autophagy under these situations may serve to removeoxidized and damaged proteins and organelles, and thus maintaincellular survival. Nevertheless, if the oxidative damage is wide,autophagy can provide a way to cell death (Scherz-Shouval andElazar, 2009).

In spite of description of ROS-induced autophagy, only a fewdirect factors that adjust autophagy under oxidative stress arediscovered so far. In a study by Eisenberg-Lerner and Kimchi,death-associated protein kinase (DAPK) and protein kinase D(PKD) were introduced as the regulators by revealing their rolein the process of autophagy in general, and particularly duringoxidative stress (Eisenberg-Lerner and Kimchi, 2012a). Later,it was emphasized that both PKD and DAPK were needed for the

induction of autophagy during oxidative stress, and that PKDproceeds as a downstream effecter of DAPK in ROS-inducedautophagy (Eisenberg-Lerner and Kimchi, 2012b). Recently, autop-hagy was identified to be regulated by mitochondrial superoxide(Chen et al., 2009). Based on Liu's study, oxidized low-densitylipoproteins upregulate proline oxidase (POX) to start ROS-dependent autophagy, commonly via the generation of superoxidewhich is a specific member of ROS produced by POX (Liu et al.,2005).

Several studies showed that ROS formation may mediateapoptosis and/or autophagy induction in several types of cancercells (Wang et al., 2011; Wong et al., 2010). In this case, it has beenfound that curcumin can induced autophagy in HCT116 humancolon cancer cell mediated by ROS generation (Lee et al., 2011).A study indicated that Resveratrol effectively suppressed thegrowth of HT-29 and COLO 201 human colon cancer cells throughinvolvement of Caspase-8/Caspase-3-dependent apoptosis whichis also mediated by ROS-triggered autophagy (Miki et al., 2012).It was also shown that under starvation situations, cells produceROS, specifically H2O2, which is essential for autophagosomeformation and autophagic degradation as a survival pathway(Scherz-Shouval et al., 2007).

Autophagy is often involved in several anticancer treatmentsthat are armed against uncontrollable division of tumor cells byvast generation of ROS (Kimmelman, 2011). Photokilling of cancercells is conducted thorough irradiation of visible light to photo-sensitizing agents accumulated in the specific cell organelles. Thisprocess, also called photodynamic therapy (PDT) renders a photo-physical reaction in the targeted areas that leads to production ofmultiple cytotoxic ROS (Dolmans et al., 2003; Kessel et al., 2012).Depending on the molecular context of PDT target tissues, differ-ent signaling pathways of autophagy induction can result incontrasting responses (Reiners et al., 2010). Decreased accumula-tion of oxidatively damaged macromolecules and increased clear-ance of nonfunctional cellular agents have been observed afterPDT-induced autophagy. Silencing of autophagy-related protein-5(Atg5) or Atg7, two critical autophagy genes, is related withincreased apoptotic photo killing; thus, it can be concludedthat autophagy may contribute to cancer defending mechanismsagainst ROS-based anticancer therapies (Dewaele et al., 2011;

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Table 1The common pro-autophagy drugs on cancer cells.

Drugs Targeted cells Outcomes References

Arsenic trioxide(As2O3)

Malignant glioma cells, leukemia cells,ovarian Carcinoma cells

Dose-dependent cell arrest in all cell types Goussetis et al. (2010), Kanzawa et al.(2003), and Smith et al. (2010)

Chloroquine Melanoma cell lines, glioma cells Induced cytotoxicity and concentration-dependent death inmultiple cell lines

Egger et al. (2013) and Geng et al.(2010)

Curcumin Endothelial cells, oral cancer cells Induction of autophagy while preventing oxidative stress as anantioxidant

Han et al. (2012) and Kim et al.(2012)

Fullerene C60 Normal and drug-resistant cancer cells Killing both normal and drug resistant cell lines Wei et al. (2010) and Zhang et al.(2009)

Panitumumab(EGFRantibody)

Colon cancer cells Reduced cell prolifration Giannopoulou et al. (2009) andKalofonos et al. (2009)

Esomeprazole Melanoma cells Induced accumulation of ROS as well as autophagosomes Marino et al. (2010)RecombinanthumanHMGB1

Leukemia cells, pancreatic cancer cells Increased expression of the autophagic markers andautophagosome formation

Liu et al. (2011) and Tang et al. (2010)

Resveratrol Breast cancer cells, myelogenous leukemiacells, gastric cancer cells

Triggers death and arrests cell proliferation while promotingautophagy

Puissant et al. (2010), Scarlatti et al.(2008), Signorelli et al. (2009)

Suberoylanilidehydroxamicacid

Chondrosarcoma cells, Hela S3 cells Induction of nonapoptotic cell death with autophagycharacteristics

Cao et al. (2008) and Yamamoto et al.(2008)

Sulforaphane Prostate cancer cells Increased autophagy associated with enhanced up regulation ofautophagosomes

Herman-Antosiewicz et al. (2006)

Tamoxifen Mammary carcinoma cells ROS-dependent inhibition of cell replication and vastaccumulation of autophagic vacuoles

Bursch et al. (1996) and De Medinaet al. (2009)

Temozolomide malignant glioma cells Inhibition of cell viability, remarkable increase in disruption ofcell cylcle and autophagic cell death

Kanzawa et al. (2004) and Milanoet al. (2009)

Valproic acid Malignant glioma cells Induced autophagy independent of apoptosis Fu et al. (2010)






Mroz et al., 2011). Although the mentioned pro-survival functionof autophagy can be provoked in particular conditions, furtherinvestigations have demonstrated that PDT-mediated autophagyin cancer cells with defective apoptotic pathways navigates the cellinto pro-death settings. This data suggest that autophagy is theprimary requirement of efficacious photo killing in tumor cellswith inoperative cell death mechanisms; therefore, the ultimateaftermath of autophagy in PDT is directly depended on thefunctionality of cell apoptotic systems (Kessel et al., 2006).

As a promising treatment for patients with acute promyelocyticleukemia, arsenic trioxide (ATO) mechanism is mostly reliedon a multiplex of ROS generating pathways that induce apoptosis(Beauchamp et al., 2011). However, studies are suggestive of ATO-mediated autophagic cell death besides other oxidative renderedapoptotic cascades (Goussetis et al., 2013). Recent studies haveshown a disruption in Bcl-2/Bcl-XL expression along with loss ofmitochondrial membrane potential in several tumor cell lines(Momeny et al., 2010; Selvaraj et al., 2013; Zheng et al., 2010).Enlightening the role of ATO in malignant glioma autophagic celldeath, Kanzawa et al. have reported BNIP3 as a central factor(Kanzawa et al., 2005). Hence, it can be concluded that Bcl-2/Bcl-XL down-regulation and BNIP3 up-regulation are potent targets ofautophagy. A study by Chiu et al. revealed that ATO inducedinhibition of Survivin, a protein overexpressed in glioma cells,could trigger both apoptosis and autophagy in human glioma cellline U118-MG (Chiu et al., 2011). An in vitro investigation ofhuman T-lymphocytic leukemia and myelodysplastic syndromecell lines has indicated the up-regulation of Beclin-1 as an involvedmechanism in ATO autophagic cell death (Qian et al., 2007).However, analysis of ATO induced death on transforming growthfactor-β signaling mediators in ovarian cells by Smith et al.demonstrated the role of SnoN in promotion of ATO mediatedautophagic cell survival as a beclin-1-independent pathway (Smithet al., 2010). With regard to the diversity of ATO triggered path-ways in apoptosis and autophagy mediated cell death, it seemsthat ATO response is cell type dependent.

In addition, 2-methoxyestradiol (2-ME) has potent anti-angio-genic, anti-proliferative and ROS generating capacities, as a resultof its potential in inhibiting both mitochondrial respiratory chainand SOD (Fukui and Zhu, 2009). Assessments of the in vitroantimitotic activities of 2-methoxyestradiol-bis-sulphamate onthe non-tumorigenic MCF-12A breast epithelial cell line endorsethe differential death mechanisms of this agent (Visagie andJoubert, 2012). 2-Ethyl-3-O-sulphamoyl-estra-1,3,5 [16-tetraene(ESE-16)], a novel 2-ME analogue is designed to improve anti-proliferative properties (Visagie and Joubert, 2012). Theron et al.study on the tumorigenic human epithelial cervical (HeLa) cellsclarified ESE-16 ability of autophagic and apoptotic cell deathinduction via targeting microtubule integrity and metaphase block(Theron et al., 2013). Moreover, the results of a recent study byYang et al. are redolent of RNA-dependent protein kinase role inenhancing the anti tumor effects of 2-ME-induced autophagy inthe control of osteosarcoma (Yang et al., 2013). Determining thespecific vulnerability of cancer cells to ROS triggered apoptosis orautophagy after exposure to 2-ME necessitates future investiga-tions. With regard to the importance of autophagy in cellularmechanisms of survival, further clinical research are vital toexplicate the therapeutic utilization of this pathway as a chemo-prevention strategy in early and advanced phases of disease.

8. Approaches to generate ROS as cancer therapy

The possession of higher capacity in coping with ROS inducedstress might make the use of direct or indirect ROS generatorspossible in preferential killing of cancer cells and ameliorating the

therapeutic course of the disease toward a selective method(Diehn et al., 2009). Hence, in order to inflict cancer cells withlethal damages of oxidative stress, treatment strategies triggerapoptosis by either utilizing ROS producing agents or strikingof tumor cell strongholds (Benhar et al., 2002). The use of ROSgenerating drugs is now widespread as the main or adjuvantmethod in treating cancer; therefore, these agents are reviewed ina separate topic. Penetration of cell defend lines can be achieved intwo principal ways: inhibition of antioxidants or demotion ofintrinsic capacity of buffering oxidants (Fruehauf and Meyskens,2007). Clinical trials have observed a remarkable attenuation ofROS insults in confront with antioxidant systems. Shi et al. in arecent study of formaldehyde-induced toxicity in A549 humanlung cancer cell line reported reduced levels of ROS and DNA–protein cross-links with selenium pretreatment (Shi et al., 2012). Astudy of rat alveolar macrophages by Pathania et al. demonstratedsuppressed ROS content in response to vitamin E supplementation(Pathania et al., 1999). Thus several researches have tested theability of antioxidant inhibitors such as ATO and 2-ME in compro-mising cellular ROS coping potentials (Han et al., 2010; She et al.,2007). Involvement of these agents in multi biological pathwaysmay also enable them to deploy their toxic effects by interfering incellular reducing buffering systems as well as further ROS genera-tion. For instance, besides inhibiting glutathione peroxidase anti-oxidant, ATO can also render vast generation of ROS via impairingthe mitochondrial respiratory chain (Dai et al., 1999; Lu et al.,2007). GSH as the leading component of thiol buffer plays animportant role in survival of tumor cells targeted by cisplatin orATO (Balendiran et al., 2004; Galluzzi et al., 2012). Increasedapoptotic effect of ATO in cells such as HL-60 and arsenic resistantNB4 cell lines is also observed in its concomitant use withButhionine sulfoximime (BSO) that can lower GSH content byinhibiting glutamylcysteine synthetase (Duechler et al., 2008; Hanet al., 2005). Enhanced responses against tumor cells in synergisticuse of BSO and melphalan supports the strategy of combiningGSH-depleting agents with chemotherapeutic drugs as a success-ful method (Anderson et al., 2000). Kimani et al. reported thatcombination of antioxidant inhibitors and photodynamic therapy(PDT) may result in higher levels of ROS generation and apoptosisin MCF-7 cancer cells compared to PDT alone (Kimani et al., 2012).Considering that the overall oxidative state of cell is controlled byboth ROS production and elimination; hence, appropriate resultsin killing cancer cells depends on using a proper combination ofantioxidant inhibitors and ROS generating factors.

8.1. ROS-generating drugs as chemotherapeutics in cancer

Higher level of oxidative stress in tumor cells compared tonormal tissue cells makes it reasonable that production of acancerous tissue is more dependent to defense systems such asantioxidants than normal cells (Hileman et al., 2004). Based onthis notion researchers have set strategies to increase ROS content,weather by attenuating the prominent role players of the cancerdefense line or by raising the ROS level as a direct target (Pelicanoet al., 2004). Currently, several anticancer therapeutic agents areknown which can stimulate oxidative stress, and thus kill tumorcells in a preferential manner. Cisplatin, arsenic trioxide, anthra-cyclines and bleomycin are among the most common applied ROSgenerators in therapy strategies (Zhang et al., 2009). Cisplatin is ahighly effective ROS generator and the first member of a class ofanti-cancer drugs, called platinum containing agents. The plati-num atom of this chemical substance can mediate DNA crosslinking by binding to guanine bases and promoting apoptosis asa result (Huang et al., 1995). Studies suggest that TNF-α inducedROS production and also activation of NADPH oxidase, which has anotable effect on signaling pathways of oxidative stress, are two

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probable mechanisms of cisplatin mediated cell death (Kim et al.,2010; Woo et al., 2000). The remarkable efficacy of ATO ininhibiting acute promyelocytic leukemia growth led to furtherinvestigations on the acting mechanisms of this agent. Althoughits exact site of action is still not completely clear, the drug issupposed to disrupt mitochondrial membrane permeability byincreased production of intracellular ROS, notably superoxides(Choi et al., 2002). Daunorubicin and Doxorubicin are two mem-bers of anthracycline family which trigger apoptosis by increasingintracellular ROS. Daunorubicin ROS products interact with JNK/Stress-activated protein kinase (SAPK) pathway while doxorubicincauses mitochondrial damage by immense generation of super-oxide and hydrogen peroxide (Laurent and Jaffrézou, 2001;Zhang et al., 2012). Studies demonstrate that bleomycin initiatesoxidative stress induced cell death by regulating caspase-8 andcaspase-9. In late phases Fas can also amplificate this mechanismin epithelial cell apoptosis (Wallach-Dayan et al., 2006).

8.2. Radiation induced-ROS as cancer therapy

A vast number of researches suggest that the potential ofcancerous tumors in neutralizing and defending against ROSagents can directly affect their chemotherapy resistance level.Therefore, diverse anti-cancer drugs have been developed toincrease the ROS production as a direct target or by interactionwith ROS scavenging enzymes. Efforts in investigation of solutionsintensifying radiation therapy have helped researchers developtwo strategies, dose escalation of radiation therapy and introduc-tion of a new class of cytotoxic chemotherapy drugs called radio-sensitizers and enhancers. Among all these anti-cancer agentsProcarbazine, Buthionine sulfoximine (BSO), and Motexafin gado-linium (MGd) are well known examples that some have beeneven approved by the U.S. Food and Drug Administration (FDA)(Renschler, 2004).

Procarbazine was one of the first developed drugs with ROS-generating properties (Berneis et al., 1963). It is hypothesized thatthe production of hydrogen peroxide by oxidation of procarbazinein aqueous solution plays a critical role in the cytotoxic mechanismof this agent as a new class of tumor inhibiting compounds (Guptaet al., 2012). Early screening conducted in mice and rats showedthe procarbazine ability in prevention of transplantable tumorsgrowth including Walker carcinoma 256 and Ehrlich carcinomaand also reduction of Ehrlich ascites cells mitoses (Schwartz et al.,1967). The MOPP regimen, a combination of Mustargen withOncovin, Procarbazine and prednisone, has achieved long termremissions in more than 80% of patients. The synergistic effectsof Procarbazine with radiation therapy has ranked it as a topselection drug primarily for the treatment of Hodgkin's and non-Hodgkin's lymphomas, and also brain tumors since its earlyapproval. Considering that procarbazine can easily pass the bloodbrain barrier with a balanced concentration between plasma andthe cerebrospinal fluid, its effects has been widely researchedin brain tumors, especially in patients with glioma (Armand et al.,2007). Despite limited usage, malignant melanoma, multiplemyeloma, and lung cancer has also been targeted by Procarbazine(Falkson et al., 1965).

BSO is an efficacious and specific inhibitor of gamma-glutamyl-cysteine synthetase which is commonly up-regulated in tumorsresistant to chemotherapy (Griffith, 1982; Renschler, 2004).In phase I of clinical trials, it was claimed that the administrationof BSO is safe and notable reduction of GSH level (o10% ofpretreatment value) in cancer patients was seen (Bailey et al.,1997). In a similar conclusion, depletion of GSH content of tumorcells increases the sensitivity to agents mediating cytolysis suchas sesquiterpene lactones, platinum compounds, alkylators andalso ROS generated by acute phase leukocytes (Arrick et al., 1983;

Meijer et al., 1992). A recent research carried out by Maeda et al.suggested that the combination of BSO and arsenic trioxide(As2O3), a potent ROS generator that has been shown to enhanceclinical remission in cases of acute promyelocytic leukemia, canresult in successful treatment of advanced solid tumors (Yanget al., 1999). in vitro studies of this combination has also shownimprovements in inhibition of growth in cell lines of prostate,lung, bladder, colon, cervix, and kidney cancers (Yang et al., 1999).

MGd is an aromatic macrocycle with radio-enhancing proper-ties which has a unique effect on increasing the whole brainradiotherapy index in brain metastases (Khuntia and Mehta,2004). In the molecular pathway, MGd targets and inhibitsoxidative stress-related antioxidant enzymes such as thioredoxinreductase. It is a hydride donor in re-reduction of GSSG to GSH,therefore, also is suggested to act as an indirect antioxidantby restoring the antioxidative power of glutathione. Hence, it isthought that the interactions of MGd will ultimately lead to areduced repair ability of cancerous cells in a clash against oxidativedamage induced by radiation and an increase in responsiveness toa variety of tumor treatments (Bradley et al., 2013a; Hashemyet al., 2006). in vitro studies on cancer cell lines of multiple sourceshave shown that in redox cycling and presence of oxygen, MGdforms superoxide and several other ROS by accepting electronsfrom various cellular reducing metabolites. The improving effectsof MGd combination treatment with ionizing radiation have beenobserved in some controlled clinical trial investigations (Magdaand Miller, 2006). Mehta et al. in a phase III randomized trialassessed neurocognitive function and survival rate in two groupsof patients receiving whole brain radiation with or without MGd(Mehta et al., 2003). There were no remarkable differences in theoverall results; however, neurologic findings demonstrated MGdtreatment benefits and an improved time to neurologic progres-sion in all patients (Mehta et al., 2003). To improve the finaloutcomes, Bradley et al. administered MGd prior to daily radiation,in phase II of a clinical trial; in contrast to the study conductedby Mehta et al., the results did not support the role of thisradiosensitizing agent in enhancing the survival rate of pediatricpatients suffering from newly diagnosed intrinsic pontine gliomas(Bradley et al., 2013b).

9. Targeting mitochondrial ROS as cancer therapy

Mutated cancer cells with associated disruption of mitochon-drial transport chain are more likely to exhibit chronic states ofmetabolic oxidative stress and thus have a higher susceptibilityto ROS induced apoptosis (Li et al., 2013). This escalated level oftumor cells sensitivity can be exploited for selective demolition ofcancer cells (Dilda and Hogg, 2005). Mitocans are a group of anti-cancer drugs able to specifically target and destabilize cancercells mitochondria as their achilles heel for tumor destruction byunleashing the apoptogenic potential that can suppress tumorgrowth (Neuzil et al., 2007). Superoxide formation is induced asa frequent aftermath of mitocans specific for the mitochondrialelectron transport chain inhibition, resulting in the preferentialkilling of cancer cells. Furthermore, the rare mutations of macro-molecular complexes of the electron transport chain is an indica-tion of useful targets for anti-cancer drug development (Rohlenaet al., 2013). Siedlakowski et al. have reported Pancratistatinability in selective induction of mitochondrial apoptosis inhuman breast cancer cell lines MCF-7 and Hs-578-T compared tonon-cancerous counterparts thorough mitochondrial membranepermeabilization, increased levels of ROS and decreased ATP(Siedlakowski et al., 2008). Investigation of BTG2 pathways,a tumor suppressor gene associated to cancer cell metastasisformerly, in A549 and PC3 cell lines showed that BTG2

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overexpression can synchronously increase Src reduction state andinhibit ROS production by being localized in mitochondria. Down-regulation of Src-FAK signaling also resulted in suppressed cellmigration (Lim et al., 2012). Compound K modulation of Bax andBcl-2 in HT-29 human colon cancer cells can disrupt mitochondrialmembrane potential and activate caspase 3 and 9. As a result, theintracellular generation of ROS led to a mitochondria-dependentapoptosis (Lee et al., 2010). Emodin-mediated apoptosis in humantongue cancer cells is another example of caspase-9 and caspase-3cell death concomitant with the release of cytochrome c frommitochondria and ROS generation (Lin et al., 2009). Together theemerging of recent researchers on mitochondria anti-cancer drugswhich mostly are dependent on imbalances of mitochondrialmembrane potential and ROS production emphasizes the crucialrole of mitochondria as an organelle that can be targeted inselective killing of cancer cells. Thus, the continuous research inthis area will lead to introduction of novel drugs with the leastadverse effects on normal cells.

10. Antioxidants in oxidative therapy against cancer

Although ROS formation is the primary mechanism of mostchemotherapy drugs against cancer, unfortunately, normal tissuesare also exposed to the serious side effects of these agents(Wiseman, 2005). For example, both cisplatin and anthracyclineas two common drugs of current chemotherapeutic strategies candevelop severe complications including nephrotoxicity, peripheralneuropathy and cardiotoxicity (Monsuez et al., 2010; Rajeswaranet al., 2008). Thus, to counteract ROS side effects and alleviatethe deterioration of normal tissues, a toxicity neutralizing methodwhich can enable much more patients to undergo chemotherapyregimens, may be considered beneficial in combination withchemotherapy (Lindley et al., 1999). While investigating the corre-lation between ROS, cancer and serum levels of many other relatedfactors, contrasting levels of antioxidants in different tumorsintrigued researchers to a new influencing factor on cancer devel-opment that could be beneficial in chemotherapy (Table 2) (Conklin,2000). A few reports show that some types of cancers have elevatedlevels of antioxidants; however, studies propose that this increasedactivity of antioxidant systems is a response of cancerous cells tothe chemotherapeutic agents (Järvinen et al., 2000; Portakal et al.,2000). Biochemical evaluations demonstrated that in most humancancers antioxidant levels are below the normal range. Increasedoxidative stress and low antioxidant status are even seen before theinitiation of oncology treatment in patients with tongue and lungcancers (Klarod et al., 2011; Sharma et al., 2009). Therefore, it maybe possible that the diminished amounts of antioxidants areable to make cells susceptible to carcinogenic agents. The debatearisen from the role of antioxidants as preventive agents of cancer

progression and their efficacy on altering patients' prognosis hasbecome the focal point of several researches (Borek, 2004).The inverse relation of cancer risk with consumption of dietarysupplements and foods with high levels of antioxidants is shown insome epidemiological and interventional studies. Selenium, carote-noids, vitamin E and C are among antioxidants that are supposed tohave anti-cancer effects (Borek, 2004; Watson and Leonard, 1986).Antioxidants such as vitamin E, D and C can cause selectiveinduction of apoptosis in tumor cells but not in normal cells andprevent metastatic spread and angiogenesis (Hong et al., 2007;Mathiasen et al., 1999; Patacsil et al., 2012). Han et al. reported anattenuated risk of pancreatic cancer in association with dietaryintake of selenium (Han et al., 2013). In another study Gopalak-rishna et al. have focused on the crucial role of selenium as aninhibitor of tumor promoting signals generated by enzymes such asprotein kinase C. The study concluded that advanced malignanciesmay be developed by a resistance to selenium (Gopalakrishna andGundimeda, 2002). Vitamin E succinate inhibition of colon cancergrowth andmetastases both in vitro and in vivo via tumor apoptosisand suppression of cell proliferation was manifested in a clinicaltrial by Barnett KT et al. (Barnett et al., 2002). An analysis of eightcohort studies conducted by Eliassen et al. proved that high levelsof circulating carotenoids may reduce the risk of breast cancer(Eliassen et al., 2012). Adverse side effects of cancer therapy tonormal cells such as fibrosis and mucositis were shown to beimproved by patients using vitamin E and C (Citrin et al., 2010).On the other hand, there are also opposing data to the posi-tive properties of antioxidants as a cancer adjuvant treatment.To compare the enhancing effects of antioxidants with placeboBjelakovic et al. reviewed all available related randomized trials inprevention of gastrointestinal cancers. No evidence was foundin accordance with the antioxidants cancer prevention hypothesis.On the contrary, results showed an overall increase of mortality inpatients consuming antioxidant supplements (Bjelakovic et al.,2004). Cortes Jofre et al. also did not recommend the use of anycombinations of vitamin supplements to decrease lung cancermortality in healthy people. There are some documents revealinga small increase of mortality and risk in lung cancer patients whoare either smokers or exposed to asbestos and use beta carotenesupplements (Cortés Jofré et al., 2012). Although studies haveachieved valuable results from trials, determining the ability ofantioxidants to reduce cancer risk has not been totally conclusiveand further research on this topic is still needed to resolve thecurrent controversies.

11. Conclusion

ROS is a potential double-edged sword in progression and pre-vention of cancers (Fig. 8). Regarding to the dosage and duration of

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Table 2The common antioxidants involved in clinical cancer trials.

Antioxidantsupplement

Targeted patients Outcome References

Vitamin A Lung cancer No difference in survival of smokers, protective in nonsmokers Feskanich et al. (2000) andvan Zandwijk et al. (2000)

Vitamin C Terminal cancer patients Lower scores for appetite loss, fatigue, nausea/vomiting and pain Yeom et al. (2007)Vitamin E Primary cancer prevention No overall benefit in mortality, may increase all-cause mortality

in high doseLee et al., (2005) and Miller et al. (2005)

Selenium Prostate cancer Reduced risk, no prevention Etminan et al. (2005) and Lippman et al.(2009)

Coenzyme Q10 End-stage cancer Improved survival Hertz and Lister (2009)Melatonin Solid tumor cancer

patientsSubstantial reduction in risk of death with no severe adverseevents

Mills et al. (2005)

Flavonoids Colorectal cancer Reduced recurrence rate of colon neoplasia Hoensch et al. (2008)






ROS and also the type of cell, all process of cell life includingproliferation, or apoptosis and necrosis are specifically influencedby temporary changes in ROS concentrations and the affectedsignal transduction pathways. It can be concluded that cancer cellscontrol oxidation state by balancing the involved factors at higherlevels than normal cells. Thus, to impede this accumulation of ROSand maintain a higher level of tolerance, tumor cells initiatevast up-regulation of multiple antioxidant systems such as SOD,catalase, and peroxidases. Combination therapies in cancerpatients could be achieved in order to either increase the intensityof ROS, or to perform different cytotoxicity mechanisms. There-fore, there is an opportunity to extend handling strategies inwhich ROS can either induce or inhibit cancers in differentconditions.

Declaration of interest

The author(s) report no conflicts of interest. The authors aloneare responsible for the content of the paper.

Acknowledgments

This study was supportQ10 ed by Tehran University of MedicalSciences.

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Fig. 8. The role of ROS in creation and therapy of cancer.






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