Reactive Oxygen Species: Synthesis and Their Relationship with Cancer-A Review

Ayesha Noreen1, Dilara A. Bukhari2 and Abdul Rehman1,*

1Department of Microbiology and Molecular Genetics, University of the Punjab, New Campus, Lahore 54590

2Department of Zoology, GC University Lahore, Lahore 54590

ABSTRACT

The reactive oxygen species (ROS) can be generated by intake of environmental pollutants, smoke, tobacco, xenobiotic, drugs, medical materials, radiations, pesticides, industrial solvents and ozone. The processes running in the cell membranes, peroxisomes, mitochondria and endoplasmic reticulum also generate ROS. ROS can be activated by numerous external factors, and play an important role in cancer growth and metastasis. ROS and tumor cell interaction could activate the signalling pathways, promoting cell proliferation, invasion, inducing angiogenesis, inflammation and cellular transformation in cancer. A better understanding into the mechanism of ROS in cancer progression might be useful for the development of biomarkers and therapeutic strategies. The objective of this review was to summarize the roles of ROS in different stages of cancer, cell invasion, angiogenesis and metastasis.

Article Information

Received 12 March 2018

Revised 02 June 2018

Accepted 10 July 2018

Available online 24 August 2018

Authors’ Contribution

AN collected information and wrote the manuscript. DAB helped in manuscript preparation. AR conceived the idea and wrote and edited the manuscript.

Key words

ROS, Cancer, Cell signaling, Cancer prevention.

DOI: http://dx.doi.org/10.17582/journal.pjz/2018.50.5.1951.1963

* Corresponding author: [email protected]

0030-9923/2018/0005-1951 $ 9.00/0

Copyright 2018 Zoological Society of Pakistan

Introduction

 

Sources of reactive oxygen species (ROS)

Oxygen is an essential survival component of human life; however, it is also an alarming sign for human life due to the production of toxic agents (Pramanik and Pandey, 2013). During ATP synthesis in mitochondria electrons transfer from NADPH and succinate to molecular oxygen and may leak out of the electron transport pathway. These electrons react with O2 to form reactive oxygen species (ROS) (Fig. 1) which are highly reactive (Gogvadze et al., 2008; Murphy, 2009; Andrea and Chandel, 2014), move through mitochondrial pore into the cytoplasm (Storz, 2006; Andrea and Chandel, 2014) and converted into H2O2 by superoxide dismutase (SOD2, SOD3) of mitochondrial matrix or of cytosol (SOD1) (Brown and Bicknell, 2001; Rhee, 2006; Gupta et al., 2012; Andrea and Chandel, 2014; Costaa et al., 2014). Under normal circumstances, cellular antioxidants defense mechanisms minimize any damage. ROS are also formed during non-enzymatic processes. For example, exposure to UV light and ionizing radiation causes ROS formation.

Mitochondria are not only generator of ROS while the neutrophils and macrophages also generate ROS by oxidase enzyme bounded in the plasma membrane (NADPH-oxidase) controlled by the GTPase Rac1 downstream of the proto-oncogene Ras (Sundaresan et al., 1996; Brown and Bicknell, 2001; Ishimoto et al., 2014).

ROS can be divided into major two types; first form carrying one or two unpaired electron while the second form having no unpaired electron is also highly reactive due to its conversion into radical form. ROS can be generated by the intake of extracellular agents i.e., all types of environmental pollutants such as smoke, tobacco, xenobiotics, drugs, medical materials, radiations, pesticides, industrial solvents, ozone etc. (Ebadi, 2001; Choudhari et al., 2014) and also generated from the mechanisms working in various organelles of the body i.e., NADPH oxidase complex in the cell membranes, peroxisomes, mitochondria, endoplasmic reticulum (Inoue et al., 2003; Gupta et al., 2012; Choudhari et al., 2014; Zhou et al., 2014), phagocytosis, arachidonate pathways, exercise, ischemia/reperfusion injury by oxygen metabolism, immune responses and inflammation (Miguel and Cordero, 2012; Salman and Ashraf, 2013; Choudhari et al., 2014; Okon and Zou, 2015).

Peroxisomes contain xanthine oxidase enzyme for the generation of superoxide and H2O2 (Bonekamp, 2009; Misra and Reddy, 2014). The former reacts with nitric oxide and produces highly reacted peroxynitrite while the later in the presence of catalase converted into harmless product i.e., water, while in the presence of metallic catalyst, it transformed itself into more reacted hydroxyl radicals (Szabo et al., 2007). Similarly, cell membrane synthesizes and retains various reactive oxygen species from various organelles i.e., endoplasmic reticulum (Geiszt et al., 2000; Lambeth, 2004; Bedard and Krause, 2007; Gupta et al., 2012; Zhou et al., 2014).

 

Role of mitochondria in reactive oxygen species production

According to Haas et al. (2008), the level of CoQ in mitochondria can be used as biological marker; its deficiency reduces activity of mitochondrial respiratory enzymes, low expression of oxidative phosphorylated protein, lower mitochondrial membrane potential, enhances the ROS production, mitochondrial permeabilization, mitophagy of dysfunctional mitochondria, reduced growth rates and cell death (Rodriguez-Hernandez et al., 2009; Cotan et al., 2011; Miguel and Cordero, 2012). During respiratory damage in the cancerous cells, at the inner membrane of the mitochondria, electron having low coupling capacity causes more release of electron to form superoxide radicals that move into the cytosol, thus stimulating neighboring mitochondria for further ROS production. This phenomenon is known as “ROS-induced ROS-release”, working as positive feedback mechanism for ROS generation to damage mitochondria (Pelicano et al., 2003; Zorov et al., 2006; Miguel and Cordero, 2012).

 

Relationship between cancer and ROS

Oxidative stress is the condition when an unbalance of oxidants and antioxidants (which remove oxidants) occur which consequently enhanced the production and accumulation of oxidants within the body (Salman and Ashraf, 2013) i.e., hydroxyl radical, superoxide radical, nitric oxide radical, lipid peroxyl radical, peroxy and alkoxy radicals, oxygen derived non-radical species like hydrogen peroxide and singlet oxygen (Circu and Aw, 2010; Stojnev et al., 2013; Choudhari et al., 2014). Mammalian cells utilize oxygen during aerobic respiration normally generated the oxygen radicals continuously for bactericidal and other cell defending activities, and their level maintained by the cell scavenging system to stop alteration in protein, lipids and DNA (Klaunig and Kamendulis, 2004; Choudhari et al., 2014; Ma et al., 2014). During aerobic respiration 4-5% of molecular oxygen is converted to reactive oxygen species (Salman and Ashraf, 2013) and over production of these radicals may cause various type of diseases i.e., cancer (Brown and Bicknell, 2001; Benhar et al., 2002; D’Autreaux, and Toledano, 2007; Fruehauf and Meyskens, 2007; Veal et al., 2007; Winterbourn, 2008; Alexander et al., 2010; Gupta et al., 2012; Choudhari et al., 2014). Carcinogenesis is known as the cell cycle disease consisting of various steps i.e., a healthy cell intake non genotoxic and genotoxic agents that cause various mutation. If the damage occurred, due to mutation, within DNA molecules is not high then move on to newly dividing cell by malfunction of the cell cycle machinery producing neoplastic, if it’s to high then stimulate the cell death (Fig. 2) machinery by triggering p53 for apoptosis and cell necrosis (Sandhu et al., 2000; Miguel and Cordero, 2012; Choudhari et al., 2014; Ma et al., 2014).

Damages caused by ROS in carcinogenesis

Mitochondria are the major source of the generation of ROS, mainly superoxide due to malfunctioning of electron transport chain, later on reduced to hydrogen peroxide and hydroxyl radicals. These ROS cause the DNA mutations which can induce guanine to thymine trans versions or vice versa (Lunec et al., 2002), alkali labile sites, oxidized purines and pyrimidine’s, instability formed directly or by repair processes (Dizdaroglu et al., 2002; Cooke et al., 2003; Jaruga et al., 2004; Choudhari et al., 2014). These mutations mostly affect GC base pairs i.e., base pair substitutions, deletions and insertions are less occurring, while AT base pair cause rare mutations; single or double strand breaks and exchanges of sister chromatid, and all these genetic instability results the inactivation of tumor suppressor genes or enhance the expression of proto oncogenes strengthen the cancer (Szatrowski and Nathan, 1991; Retel et al., 1993; Brown and Bicknell, 2001). The 8-hydroxy-2’-deoxyguanosine in case of invasive ductal cancer is 10 times highly occurring as compared to the noninvasive (Wiseman and Halliwell, 1996; Brown and Bicknell, 2001). Brain cells are highly susceptible to harmful effect of ROS due to their low ability for cellular regeneration and enhanced metabolic rate (Waris and Ahsan, 2006; Choudhari et al., 2014).

Effect of ROS on different stages of cancer

The oxidative damage has been linked to at least 100 human diseases because each and every tissue of the body can undergo malignant state by activation of proto oncogenes into carcinogenic oncogenes, and having various type of cancer (Sugimura, 1998; Waris and Ahsan, 2006; Choudhari et al., 2014). Cell cycle normally controlled by set of proteins i.e., cyclins and cyclin-dependent kinases (CDKs) which regulate cell-cycle growth that are under the control of cyclins and CDK inhibitors i.e., p21 and p27 inhibit the further progression of the cell cycle whereas they also activate CDKs of G1 phase (Gupta et al., 2012). Broadly, cancer contains three major stages; firstly, initiation that includes non-lethal DNA damage; to remove this error cell stops its cell cycle for further growth and later on resumes its activity (Yano et al., 2009); secondly, the promotion stage that expands the initial stage by cell growth, suppressing the apoptosis, reducing antioxidants function, promoting free radicals generation that cause the loss of cell homeostasis and construct nodules, polyp or the papilloma and thirdly, the progression of chronic DNA damage, causes genomic instability which leads to malignant transformations by failures in metabolic activity and provoking a high ROS generation (Waris and Ahsan, 2006; Kryston et al., 2011; Miguel and Cordero, 2012).

ROS induces signaling cascades

Receptor tyrosine kinases (RTKs) cascade phosphorylation, initiated by ROS that were activated by various growth factors (i.e., epidermal growth factor, platelet derived growth factor, fibroblast growth factor as well as cytokines, tumor necrosis factor, γ-interferon and interleukins) in no phagocytic cells (Waris and Ahsan, 2006; Behrend et al., 2003; Ahn et al., 2014). The two protein families which control signal transduction pathways by ROS activation are; firstly, the mitogen activated protein kinase (MAPK) that phosphorylates serine or threonine residue to transduce message (in the form of gene expression, mitosis, proliferation, motility, metabolism, and programmed cell death) from cell membrane to nucleus of the cell, and further divided into three major groups, the extracellular signal-regulated kinase, the c-Jun NH2-terminal kinase, and the p38 MAPK that control proliferation, differentiation, and apoptosis, respectively (Wada and Penninger, 2004). Secondly, the redox sensitive kinases which contain cysteine motifs i.e., thioredoxin, nuclear signaling factors such as Ref-1 and transcription factors i.e., AP-1, NF-κB, Nfr-1, Egr-1, all are plying critical role for DNA synthesis, and cell growth. The retardation in these factors arrests the cell cycle to proceed (Cook et al., 2004; Waris and Ahsan, 2006; Ahn et al., 2014).

Cell promotes mitosis by enhancing the expression of cyclin D1 and cyclin dependent kinase by increasing the activation of AP-1 (Salman and Ashraf, 2013; Ahn et al., 2014). In carcinogenesis, NF-κB plays a very important role for the cell survival and its proliferation during activated state by extracellular stimulating agents for the cell growth and retard apoptotic pathways activation (Klaunig and Kamendulis, 2004; Waris and Ahsan, 2006; Ahn et al., 2014).

ROS and cancer cell proliferation

Abnormal cells increase oxidative stress within the cell by catabolizing the thymidine to thymine and 2-deoxy-D-ribose-1-phosphate (that quickly bind with proteins to form glycated proteins) by thymidine phosphorylase (Brown et al., 2000; Brown and Bicknell, 2001). For cancer cell proliferation, more energy and building material of biological mass construction is required to fulfill their needs. Tumor cells undergo glycolysis and complex I and complex III of the respiratory chain, do not move into oxidative phosphorylation by stopping the movement of glycolytic product i.e., pyruvate by pyruvate dehydrogenase kinase 1. It also inhibits pyruvate dehydrogenase synthesis required to run Krebs cycle and enhances the lactate production. This ultimately inhibited the production of antioxidant agent generated during Krebs cycle and induces ROS generation through electron leakage by disturbing membrane potential although it’s have more energy demand for quickly growing cell. This is called as Warburg effect which is a hallmark of cancerous cells (Puntel et al., 2007; Lu et al., 2012; Costa et al., 2014).

Hypoxia is another characteristic of rapidly growing cancerous cells having more oxygen demand for massive cell growth which lack proper supply of oxygen to these cell growth, generating more oxidative stress (Chandel et al., 1998) and their survival maintained by activating hypoxia inducible factor (HIF) that increases the glucose uptake by activating glucose transporters (GLUT1 and GLUT3) for ATP synthesis. New blood vessels are constructed through the angiogenesis for more oxygen supply but these vessels are disorganized and leaky; cause the periods of hypoxia, reperfusion and ROS release (Gerald et al., 2004; Pouyssegur and Mechta-Grigoriou, 2006; Laurent et al., 2008; Costa et al., 2014).

ROS in cancer cell invasion, angiogenesis and metastasis

In tumor, there is a rapid outgrowth of tumor cells that increases blood supply by vasodilation that activates cGMP by carbon monoxide (CO) whose level increased by oxidative stress which transforms heme to biliverdin and CO by heme oxygenase-1 (Brown et al., 2000). The angiogenesis formation for energy in the form of glucose consequently enhances the levels of hypoxia inducible factor-1 (HIF-1) and causes the hypoxia (glucose deprivation) which results in more oxidative stress within cell and produces the more vascular endothelial growth factor (VEGF) (Spitz et al., 2000; Brown and Bicknell, 2001).

The last stage of cancer leads to cell invasion, angiogenesis, and metastasis by activating various factors i.e., serine proteases and its receptors, VEGF and its receptors, platelet-derived growth factor, fibroblast growth factors, epidermal growth factor (EGF), ephrins, angiopoietins, endothelins, integrins, cadherins, and transcription factors (Wang, 2001; Aggarwal et al., 2009; Gordon et al., 2010). These factors are involved in cell attachment, growth, migration by breaking the barriers between tissue through dissolving it by proteolytic enzymes i.e., matrix metalloproteinases and blood vessels formation known as angiogenesis (Jiang et al., 2001; Sternlicht and Werb, 2001; Fan et al., 2006). The high rate production of ROS, reverses its function by inhibiting the expression of genes and transcription factors participating in malignancy (Ushio-Fukai and Alexander, 2004; Ushio-Fukai, 2006; Ushio-Fukai and Nakamura, 2008; Gupta et al., 2012).

ROS role in cancer inflammation

In body defense system inflammation plays an important role for providing security to the cells, acute inflammation, is very beneficial to body, however, chronic inflammation is the alarming sign of various chronic diseases, top of which is cancer, as first time reported by Virchow (Balkwill and Mantovani, 2001; Schetter et al., 2010). Thus there is a strong relationship between chronic concentration of ROS induces COX-2, inflammatory cytokines (TNF-a, interleukin), chemokine, and pro-inflammatory transcription factors (e.g., NF-jB activation for chronic inflammation and cancer (Hussain et al., 2003; Mantovani, 2005; Mantovani et al., 2008; Colotta et al., 2009; Reuter et al., 2010; Schetter et al., 2010; Grivennikov et al., 2010; Grivennikov and Karin, 2010; Gupta et al., 2012).

ROS role in cellular transformation

There are two types of mutations for transformation of normal cell into cancerous cell; first one is gain of functional mutations of oncogenes and second one is the loss off functional mutation of tumor suppressor genes (Wang, 2010). A variety of genes mutate their function to reach malignancy state e.g., p53, Raf, retinoblastoma (Rb), protein phosphatase 2A, telomerase, Ral-GEFs, phosphatidylinositol 3-kinase (PI3K), Ras, Rac, cellular v-myc myelocytomatosis viral oncogene homolog (c-Myc), STAT3, NF-jB, and HIF-1a. Chemicals, viruses, radiation, hypoxia, and nutrient deprivation all contribute in this process (Ralph et al., 2010; Gupta et al., 2012).

Role of ROS in cancer treatment

For the cancer treatment two main strategies are applied. In ROS elevated strategy, ROS generation increases within cell, decreases the antioxidant activity while in ROS elimination strategy, ROS eaters (antioxidants) reduce ROS level and promoted the antioxidant system for cellular defense (Schumacker, 2006; Fruehauf and Meyskens, 2007; Wang and Yi, 2008; Trachootham et al., 2009; Gupta et al., 2012). ROS elevated level by radiotherapy, photodynamic or any other way from threshold limit helps in cancer therapy by apoptosis (Brown and Bicknell, 2001). Sub-lethal oxidative stress stimulates cell proliferation by activation of MAPK pathways (Wang et al., 1998; Brown and Bicknell, 2001). According to Wang et al. (2011), normal cells are exposed to Cr6+ that induces ROS generation and cellular transformation. Its production can be reduced by overexpression of antioxidants i.e., SOD1, SOD2, or CAT (Gupta et al., 2012). A combined therapy has been proved more successful.

Dual role of ROS in cancer

There is a strong relationship between ROS and cancer due to multiple reasons such as ROS promote the initiation of cancer. In cancerous cell, more ROS concentration helps in continuous expression of oncogenes and enhances the chances of error occurring in powerhouse of the cell (mitochondria). This evokes glycolytic energy generation mechanism which leads to cancer progression by activating growth factors and receptors, causes angiogenesis, inflammation, and cell transformation. ROS invasion causes mutation in tumor suppressor gene and inhibits it to perform its function and help in tumor progression and metastasis (Chandel et al., 2000; Schafer and Buettner, 2001; Seo et al., 2002; Behrend et al., 2003; Hussain et al., 2003; Boonstra and Post, 2004; Hileman et al., 2004; Ramsey and Sharpless, 2006; Takahashi et al., 2006; Wu, 2006; Liu et al., 2008; Reuter et al., 2010; Gupta et al., 2012). ROS and cancer (like as lock and key relationship), can be treated by enhancing or eliminating the level of ROS within cancerous cells. Such disturbance in optimum level of cancer causing ROS leads to death of cancerous cells (Hyoudou et al., 2006, 2008; Ozben, 2007; Seifried et al., 2007; Gupta et al., 2012). According to US Food and Drug Administration, few drugs have been used as antioxidants for pro-oxidant activity i.e., procarbazine, motexafin gadolinium, elesclomol, 2-methoxyestradiol, imexon, minodronate and histamine (Gupta et al., 2012).

In cancerous cells, ROS dosage, duration, type, and site of action help in promoting cancer cells growth or suppress their growth by cell death. Although medium concentration of ROS supply helps in cell survival and elevated concentration inhibit cell growth and kill them (Kong et al., 2000; Schafer and Buettner, 2001; Gupta et al., 2012). A low concentration of arsenite increases the expression of c-Myc, heme oxygenase-1, and NF-jB activity in breast cancer by producing ROS and promoted its growth from G1 to S phase of cell cycle (Ruiz-Ramos et al., 2009). According to Qu et al. (2011), higher the level of ROS within breast cancer cells lower the NF-JB activity, thus suppressing the cell progression (Gupta et al., 2012).

In short, in living systems ROS induces beneficial effect (i.e., responses to noxia, involve in cellular signaling systems, defense against pathogenic and induce mitogenic response at low level of ROS); or harmful effect (Valko et al., 2004, 2006). ROS causes various type of cellular damage at high level (lipids and membranes, proteins and nucleic acid) (Poli et al., 2004; Valko et al., 2006; Ma et al., 2014).

Hurdles in cancer treatment by ROS

In cancerous cell, there is a high level of ROS, and the persistent ROS concentration in it, made it resistant to external ROS stress by activating antioxidant system of cell by various transcription factors i.e., nuclear factor kappa-light-chain enhancer of activated B cells (NF-jB), nuclear factor (erythroid- derived 2)-like factor 2, cellular Ju-nanna (c-Jun), and hypoxia-inducible factor-1a (HIF-1a) (Pervaiz and Clement, 2004; Tiligada, 2006; Sullivan and Graham, 2008) e.g., resistance to H2O2, arsenic trioxide (As2O3), by enhancing the level of catalase, SOD and GSH antioxidant (Lenehan et al., 1995; Hour et al., 2004; Gupta et al., 2012). Continued oxidative stress causes resistance to apoptosis by the production of antioxidant thiol thioredoxin, metallothionein, malondialdehyde, superoxide dismutase, glutathione peroxidase and catalase (Lazo et al., 1998) and it also causes resistance to therapy (Brown and Bicknell, 2001). Our focus should be on mutual generation of ROS and harm signaling molecules associated with antioxidant system to treat cancer (Gupta et al., 2012).

ROS in cancer cell death

Cancerous cell has survival ability as inheritable character. Apoptosis, necrosis, and autophagy are the three ways used for treatment of cancer cell without harming the normal cells (Simon et al., 2000; Wochna et al., 2007; Gupta et al., 2012).

ROS and apoptosis

Apoptosis is defined as programmed cell death and is tightly controlled by cellular machinery. It is classified into extrinsic and intrinsic pathway and both are regulated by ROS (Brown and Bicknell, 2001; Ozben, 2007; Ma et al., 2014). In the extrinsic pathway, ROS required for phosphorylation of Fas ligand for its stimulation to activate death domain and caspase 8 to induce apoptosis (Denning et al., 2002; Uchikura et al., 2004; Medan et al., 2005; Reinehr et al., 2005) via ubiquitination and destruction of the FLICE inhibitory protein to retain Fas in activated state (Brown and Bicknell, 2001; Wang et al., 2007). ROS induces the activation of destabilizing proteins i.e., Bcl-2-associated X protein, Bcl-2 homologous antagonist/killer and suppresses the pore-stabilizing proteins activity i.e., Bcl-2 and Bcl-xL (Martindale and Holbrook, 2002) stimulate the cytochrome c to move out from mitochondria, construct apoptosom and activate caspase (Gupta et al., 2012; Zou et al., 2015). According to Choudhary et al. (2011), apoptosis can be induced by ROS via without caspase activity in human bladder cancer cells. It was also stimulated by administration of H2O2 to enhance the activation of caspase-3 (Gupta et al., 2012; Zou et al., 2015).

ROS and necrosis

However, a huge amount of ROS production can induce necrotic cell death. A cancerous cell can die by apoptosis and necrosis (Hampton and Orrenius, 1997). A small level of H2O2 induces the cells to caspase activation leading to apoptosis while no caspase activation occurred in case of necrosis. As a result, high ROS are produced at higher H2O2 concentration induction (Gupta et al., 2012).

ROS and autophagy

Self-eating by lysosome of distressed cellular organelles sequestrates and cytoplasmic protein aggregates help in cell survival and cell death pathways (Hippert et al., 2006; Gupta et al., 2012).

According to US Food and Drug Administration, drugs are classified into two major groups. First one is non-targeted drugs that are further classified into two classes; first those non targeted drugs that function at specific phases of cell-cycle while cell-cycle nonspecific function at any targeted point. The second is targeted drugs that are attached at targeted growth factors to stop cell growth e.g., monoclonal antibodies (rituximab, ibritumomabtiuxetan, ofatumumab, and alemtuzumab (Renschler, 2004; Gupta et al., 2012). In cancerous cells, there is over production of H2O2 that can be prevented by diphenyleneiodonium, which is an inhibitor of the flavoprotein component of the NADPH-oxidase (Brown and Bicknell, 2001).

Cancerous cells suppress antioxidant enzymes production, contact directly to ROS generating agents, and reduce buffering capacity of the cellular oxidants. Normally, cells contain less ROS stress and more activated antioxidant system to reduce oxidative damage within cell as compared to the cancerous cells (Salman and Ashraf, 2013). In vitro and in vivo combination therapy is more beneficial to kill the cancerous cells by promoting the ROS and suppressing the antioxidants (Salman and Ashraf, 2013).

Mutagenesis is one of the causing agents of chronic inflammation by activating the expression of JAK-STAT activation and JAK2. The inhibitory agents, those targeted the JAK 1-2, are very useful for suppressing the tumor progression (Verstovsek et al., 2010; Salman and Ashraf, 2013). For the therapeutic purpose electron transport chain is a good target to enhance the ROS generation within the cancerous cells and suppress antioxidant system to improve the susceptibility of ROS to induce apoptosis (Pramanik and Pandey, 2013).

Cancer prevention

Anand et al. (2008) reported that 90–95% of cancers caused by external environment i.e., advancement in life style and only 5%–10% caused by genetic defects. To overcome this disorder we have to change our lifestyle to simplest form. ROS production can be reduced by more intake of antioxidant producing fruits and vegetables (Gupta et al., 2012; Belcaid et al., 2014).

ROS and resistance therapy

Various cancerous cells develop multidrug resistance proteins in them to resist chemotherapy and radiotherapy. To overcome this problem, several researchers proposed oxidation therapy by ROS-generating anticancer agents to treat cancer (Gupta et al., 2012). According to Tsai et al. (1996), cancerous cells showed resistance against cytotoxic drugs by expressing higher level of Her-2/neu. The suppression of signaling pathways retarded the expression of Her-2/neu and cell became sensitive against these drugs; likewise mutated EGFR overexpression suppress apoptosis and retardation in EGFR signaling stop the cell growth and cell became sensitive against this drug (Nagane et al., 1998). Murillo et al. (2001) reported that the suppression in the expression of HER-2/neu stimulates p38 activity for initiation of apoptosis. So such combined strategies are very helpful to eradicate the tumor (Benhar et al., 2002; Stojnev et al., 2013; Phillips et al., 2014).

 

Conclusions

 

Oxidative stress arising from the ubiquitous production of reactive oxygen species has been implicated in the pathogenesis of various diseases including cancer. Literature review has provided some evidence of the important physiological role of ROS in normal cell function, diseases may arise where the concentration of ROS exceeds and overwhelms the body’s natural defense against them. Additionally, ROS may induce genomic alterations which affect cellular homoeostasis and may result in disease. Apoptosis, necrosis, and autophagy are the three ways used for cancer treatment of the cell without harming the normal cells in ROS presence. This disease can also be minimized by simplified life style and oxidation therapy by utilizing ROS to generate anticancer agents to treat cancer. The need is particularly pressing in developing treatments for conditions which remain difficult to treat different stages of cancer.

 

Statement of conflict of interest

The authors declare that they have no conflict of interest.

 

References

 

Aggarwal, B.B., Kunnumakkara, A.B., Harikumar, K.B., Gupta, S.R., Tharakan, S.T., Koca, C., Dey, S and Sung, B., 2009a. Signal transducer and activator of transcription-3, inflammation, and cancer: How intimate is the relationship? Annls. N.Y. Acad. Sci., 1171: 59-76. https://doi.org/10.1111/j.1749-6632.2009.04911.x

Aggarwal, B.B., Vijayalekshmi, R.V. and Sung, B., 2009b. Targeting inflammatory pathways for prevention and therapy of cancer: Short-term friend, long-term foe. Clin. Cancer Res., 15: 425–430. https://doi.org/10.1158/1078-0432.CCR-08-0149

Ahn, H., Kim, K.L.I., Hoan, N.N., Kim, C.H., Moon, E., Choi, K.S., Yang, S.S. and Lee, J.S., 2014. Targeting cancer cells with reactive oxygen and nitrogen species generated by atmospheric-pressure air plasma. PLoS One, 9: e86173. https://doi.org/10.1371/journal.pone.0086173

Alexander, A., Cai, S.L., Kim, J., Nanez, A., Sahin, M., MacLean, K.H., Inoki, K., Guan, K.L., Shen, J., Person, M.D., Kusewitt, D., Mills, G.B., Kastan, M.B. and Walker, C.L., 2010. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc. natl. Acad. Sci. USA, 107: 4153–4158. https://doi.org/10.1073/pnas.0913860107

Anand, P., Kunnumakkara, A.B., Sundaram, C., Harikumar, K.B., Tharakan, S.T., Lai, O.S., Sung, B. and Aggarwal, B.B., 2008. Cancer is a preventable disease that requires major lifestyle changes. Pharm. Res., 25: 2097–2116. https://doi.org/10.1007/s11095-008-9690-4

Andrea, G. and Chandel, N.S., 2014. Targeting antioxidants for cancer therapy. Biochem. Pharmacol., 92: 90–101. https://doi.org/10.1016/j.bcp.2014.07.017

Balkwill, F. and Mantovani, A., 2001. Inflammation and cancer: Back to Virchow? Lancet, 357: 539–545. https://doi.org/10.1016/S0140-6736(00)04046-0

Bedard, K. and Krause, K.H., 2007. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol. Rev., 87: 245–313. https://doi.org/10.1152/physrev.00044.2005

Behrend, L., Henderson, G. and Zwacka, R.M., 2003, Reactive oxygen species in oncogenic transformation. Biochem. Soc. Trans., 31: 1441-1444. https://doi.org/10.1042/bst0311441

Belcaid, Z., Phallen, J.A., Zeng, See, A.P., Mathios, D., Gottschalk, C., Nicholas, S., Kellett, M., Ruzevick, J., Jackson, C., Albesiano, E., Durham N.M., Ye, X., Tran, P.T., Tyler, B., Wong, J-W., Brem, H., Pardoll, D.M., Drake, C.G. and Lim, M., 2014. Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. PLoS One, 9: e101764.

Benhar, M., Engelberg, D. and Levitzki, A., 2002. ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep., 3: 420–425. https://doi.org/10.1093/embo-reports/kvf094

Bonekamp, N.A., Volkl, A., Fahimi, H.D. and Schrader, M., 2009. Reactive oxygen species and peroxisomes: Struggling for balance. Biofactors, 35: 346–355. https://doi.org/10.1002/biof.48

Boonstra, J. and Post, J.A., 2004. Molecular events associated with reactive oxygen species and cell cycle progression in mammalian cells. Gene, 337: 1–13. https://doi.org/10.1016/j.gene.2004.04.032

Brown, N.S. and Bicknell, R., 2001. Hypoxia and oxidative stress in breast cancer oxidative stress: Its effects on the growth, metastatic potential and response to therapy of breast cancer. Breast Cancer Res., 3: 323–327. https://doi.org/10.1186/bcr315

Brown, N.S., Jones, A., Fujiyama, C., Harris, A.L. and Bicknell, R., 2000. Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors. Cancer Res., 60: 6298-6302.

Chandel, N.S., Maltepe, E., Goldwasser, E., Mathieu, C.E., Simon, M.C. and Schumacker, P.T., 1998. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc. natl. Acad. Sci. USA, 95: 11715–11720. https://doi.org/10.1073/pnas.95.20.11715

Chandel, N.S., Vander Heiden, M.G., Thompson, C.B. and Schumacker, P.T., 2000. Redox regulation of p53 during hypoxia. Oncogene, 19: 3840–3848. https://doi.org/10.1038/sj.onc.1203727

Choudhari, S.K., Chaudhary, M., Amol R. Gadbail, A.R., Sharma, A. and Tekade, S., 2014. Oxidative and antioxidative mechanisms in oral cancer and precancer: A review. Oral Oncol., 50: 10–18. https://doi.org/10.1016/j.oraloncology.2013.09.011

Choudhary, S., Wang, K.K. and Wang, H.C., 2011. Oncogenic H-Ras, FK228, and exogenous H2O2 cooperatively activated the ERK pathway in selective induction of human urinary bladder cancer J82 cell death. Mol. Carcinog., 50: 215–219. https://doi.org/10.1002/mc.20708

Circu, M.L. and Aw, T.Y., 2010.Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic. Biol. Med., 48: 749-762. https://doi.org/10.1016/j.freeradbiomed.2009.12.022

Colotta, F., Allavena, P., Sica, A., Garlanda, C. and Mantovani, A., 2009. Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability. Carcinogenesis, 30: 1073–1081. https://doi.org/10.1093/carcin/bgp127

Cook, J.A., Gius, D., Wink, D.A., Krishna, M.C., Russo, A. and Mitchell, J.B., 2004. Oxidative stress, redox, and the tumor microenvironment. Semin. Radiat. Oncol., 14: 259-266. https://doi.org/10.1016/j.semradonc.2004.04.001

Cooke, M.S., Evans, M.D., Dizdaroglu, M. and Lunec, J., 2003.Oxidative DNA damage: Mechanisms, mutation, and disease. FASEB J., 17: 1195-1214. https://doi.org/10.1096/fj.02-0752rev

Costa, A., Scholer-Dahirela, A. and Mechta-Grigorioua, F., 2014. The role of reactive oxygen species and metabolism on cancer cells and their microenvironment. Semin. Cancer Biol., 25: 23–32. https://doi.org/10.1016/j.semcancer.2013.12.007

Cotan, D., Cordero, M.D., Garrido-Maraver, J., Oropesa-Ávila, M., Rodríguez-Hernández, A., Gómez Izquierdo, L., De la Mata, M., De Miguel, M., Lorite, J.B., Infante, E.R., Jackson, S., Navas, P. and Sánchez-Alcázar, J.A., 2011. Secondary coenzyme Q10 deficiency triggers mitochondria degradation by mitophagy in MELAS fibroblasts. FASEB J., 25: 2669-2687. https://doi.org/10.1096/fj.10-165340

D’Autreaux, B. and Toledano, M.B., 2007. ROS as signaling molecules: mechanisms that generate specificity in ROS homeostasis. Nat. Rev. Mol. Cell Biol., 8: 813–824. https://doi.org/10.1038/nrm2256

Denning, T.L., Takaishi, H., Crowe, S.E., Boldogh, I., Jevnikar, A. and Ernst, P.B., 2002. Oxidative stress induces the expression of Fas and Fas ligand and apoptosis in murine intestinal epithelial cells. Free Radic. Biol. Med., 33: 1641–1650. https://doi.org/10.1016/S0891-5849(02)01141-3

Dizdaroglu, M., Jaruga, P., Birincioglu, M. and Rodriguez, H., 2002. Free radicalinduced damage to DNA: Mechanisms and measurement. Free Radic. Biol. Med., 32: 1102-1115. https://doi.org/10.1016/S0891-5849(02)00826-2

Ebadi, M., 2001. Antioxidants and free radicals in health and disease: An introduction to reactiveoxygen species, oxidative injury, neuronal cell death and therapy in neurodegenerative diseases. Prominent Press, Arizona.

Fan, T.P., Yeh, J.C., Leung, K.W., Yue, P.Y. and Wong, R.N., 2006. Angiogenesis: From plants to blood vessels. Trends Pharmacol. Sci., 27: 297–309. https://doi.org/10.1016/j.tips.2006.04.006

Fruehauf, J.P. and Meyskens, Jr. F.L., 2007. Reactive oxygen species: A breath of life or death? Clin. Cancer Res., 13: 789–794. https://doi.org/10.1158/1078-0432.CCR-06-2082

Geiszt, M., Kopp, J.B., Vnai, P. and Leto, T.L., 2000. Identification of Renox, an NAD(P)H oxidase in kidney. Proc. natl. Acad. Sci. USA, 97: 8010–8014. https://doi.org/10.1073/pnas.130135897

Gerald, D., Berra, E., Frapart, Y.M., Chan, D.A., Giaccia, A.J. and Mansuy, D., Pouysségur, J., Yaniv, M. and Mechta-Grigoriou, F., 2004. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell, 118: 781–794. https://doi.org/10.1016/j.cell.2004.08.025

Glasauer, A. and Chandel, N.S., 2014. Targeting antioxidants for cancer therapy. Biochem. Pharmacol., 92: 90–101. https://doi.org/10.1016/j.bcp.2014.07.017

Gogvadze, V., Orrenius, S. and Zhivotovsky, B., 2008. Mitochondria in cancer cells: What is so special about them? Trends Cell Biol., 18: 165–173. https://doi.org/10.1016/j.tcb.2008.01.006

Gordon, M.S., Mendelson, D.S. and Kato, G., 2010. Tumor angiogenesis and novel antiangiogenic strategies. Int. J. Cancer, 126: 1777–1787. https://doi.org/10.1002/ijc.25026

Grivennikov, S.I. and Karin, M., 2010. Inflammation and oncogenesis: A vicious connection. Curr. Opin. Genet. Dev., 20: 65–71. https://doi.org/10.1016/j.gde.2009.11.004

Grivennikov, S.I., Greten, F.R. and Karin M., 2010. Immunity, inflammation, and cancer. Cell, 140: 883–899. https://doi.org/10.1016/j.cell.2010.01.025

Gupta, S.C., Hevia, D., Patchva, S., Park, B., Koh, W. and Aggarwal, B.B., 2012. Upsides and downsides of reactive oxygen species for cancer: The roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxid. Redox Signal, 16: 1295–1322. https://doi.org/10.1089/ars.2011.4414

Haas, R.H., Parikh, S., Falk, M.J., Saneto, R.P., Wolf, N.I., Darin, N., Wong, L.J., Cohen, B.H. and Naviaux, R.K., 2008. The in-depth evaluation of suspected mitochondrial disease. Mol. Genet. Metab., 94: 16-37. https://doi.org/10.1016/j.ymgme.2007.11.018

Hampton, M.B. and Orrenius, S., 1997. Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis. FEBS Lett., 414: 552–556. https://doi.org/10.1016/S0014-5793(97)01068-5

Hileman, EO., Liu, J., Albitar, M., Keating, M.J. and Huang, P., 2004. Intrinsic oxidative stress in cancer cells: A biochemical basis for therapeutic selectivity. Cancer Chemother. Pharmacol., 53: 209–219. https://doi.org/10.1007/s00280-003-0726-5

Hippert, M.M., O’Toole, P.S. and Thorburn, A., 2006. Autophagy in cancer: Good, bad, or both? Cancer Res., 66: 9349–9351. https://doi.org/10.1158/0008-5472.CAN-06-1597

Hour, T.C., Huang, C.Y., Lin, C.C., Chen, J., Guan, J.Y., Lee, J.M. and Pu, Y.S., 2004. Characterization of molecular events in a series of bladder urothelial carcinoma cell lines with progressive resistance to arsenic trioxide. Anticancer Drugs, 15: 779–785. https://doi.org/10.1097/00001813-200409000-00007

Hussain, S.P., Hofseth, L.J. and Harris, C.C., 2003. Radical causes of cancer. Nat. Rev. Cancer, 3: 276–285. https://doi.org/10.1038/nrc1046

Hyoudou, K., Nishikawa, M., Kobayashi, Y., Ikemura, M., Yamashita, F. and Hashida, M., 2008. SOD derivatives prevent metastatic tumor growth aggravated by tumor removal. Clin. exp. Metast., 25: 531–536. https://doi.org/10.1007/s10585-008-9165-3

Hyoudou, K., Nishikawa, M., Kobayashi, Y., Umeyama, Y., Yamashita, F. and Hashida, M.P.E., 2006. Gylated catalase prevents metastatic tumor growth aggravated by tumor removal. Free Radic. Biol. Med., 41: 1449–1458. https://doi.org/10.1016/j.freeradbiomed.2006.08.004

Inoue, M., Sato, E.F., Nishikawa, M., Park, A.M., Kira, Y., Imada, I. and Utsumi, K., 2003. Mitochondrial generation of reactive oxygen species and its role in aerobic life. Curr. Med. Chem., 10: 2495–2505. https://doi.org/10.2174/0929867033456477

Ishimoto, T., Sugihara, H., Watanabe, M., Sawayama, H., Iwatsuki, M., Baba, Y., Okabe, H., Hidaka, K., Yokoyama, N., Miyake, K., Yoshikawa, M., Nagano, O., Komohara, Y., Takeya, M., Saya, H. and Baba, H., 2014. Macrophage-derived reactive oxygen species suppress miR-328 targeting CD44 in cancer cells and promote redox adaptation. Carcinogenesis, 35: 1003–1011. https://doi.org/10.1093/carcin/bgt402

Jaruga, P., Theruvathu, J., Dizdaroglu, M. and Brooks, P.J., 2004. Complete release of (5’S)-8,5’-cyclo-2’-deoxyadenosine from dinucleotides, oligodeoxynucleotides and DNA, and direct comparison of its levels in cellular DNA with other oxidatively induced DNA lesions. Nucl. Acids Res., 32: e87. https://doi.org/10.1093/nar/gnh087

Jiang, M.C., Liao, C.F. and Lee, P.H., 2001. Aspirin inhibits matrix metalloproteinase-2 activity, increases E-cadherin production, and inhibits in vitro invasion of tumor cells. Biochem. Biophys. Res. Commun., 282: 671–677. https://doi.org/10.1006/bbrc.2001.4637

Klaunig, J.E. and Kamendulis, L.M., 2004. The role of oxidative stress in carcinogenesis. Annu. Rev. Pharma. Toxicol., 44: 239-267. https://doi.org/10.1146/annurev.pharmtox.44.101802.121851

Kong, Q., Beel, J.A. and Lillehei, K.O., 2000. A threshold concept for cancer therapy. Med. Hypotheses, 55: 29–35. https://doi.org/10.1054/mehy.1999.0982

Kryston, T.B., Georgiev, A.B., Pissis, P. and Georgakilas, A.G., 2011. Role of oxidative stress and DNA damage in human carcinogenesis. Mutat. Res., 3: 193-201. https://doi.org/10.1016/j.mrfmmm.2010.12.016

Lambeth, J.D., 2004. NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol., 4: 181–189. https://doi.org/10.1038/nri1312

Laurent, G., Solari, F., Mateescu, B., Karaca, M., Castel, J., Bourachot, B., Magnan, C., Billaud, M. and Mechta-Grigoriou, F., 2008. Oxidative stress contributes to aging by enhancing pancreatic angiogenesis and insulin signaling. Cell Metab., 7: 113–124. https://doi.org/10.1016/j.cmet.2007.12.010

Lazo, J.S., Kuo, S.M., Woo, E.S. and Pitt, B.R., 1998. The protein thiol metallothionein as an antioxidant and protectant against antineoplastic drugs. Chem. Biol. Interact., 111-112: 255-262. https://doi.org/10.1016/S0009-2797(97)00165-8

Lenehan, P.F., Gutierrez, P.L., Wagner, J.L., Milak, N., Fisher, G.R. and Ross, D.D., 1995. Resistance to oxidants associated with elevated catalase activity in HL-60 leukemia cells that overexpress multidrug-resistance protein does not contribute to the resistance to daunorubicin manifested by these cells. Cancer Chemother. Pharmacol., 35: 377–386. https://doi.org/10.1007/s002800050250

Liu, B., Chen, Y. and Clair, D.K., 2008. ROS and p53: A versatile partnership. Free Radic. Biol. Med., 44: 1529–1535. https://doi.org/10.1016/j.freeradbiomed.2008.01.011

Lu, W., Hu, Y., Chen, G., Chen, Z., Zhang, H., Wang, F., Feng, L., Pelicano, H., Wang, H., Keating, M.J., Liu, J., McKeehan, W., Wang, H., Luo, Y. and Huang, P., 2012. Novel role of NOX in supporting aerobic glycolysis in cancer cells with mitochondrial dysfunction and as a potential target for cancer therapy. PLoS Biol., 10: e1001326. https://doi.org/10.1371/journal.pbio.1001326

Lunec, J., Holloway, K.A., Cooke, M.S., Faux, S., Griffiths, H.R., Evans, M.D., 2002 Urinary 8-oxo-2’-deoxyguanosine: redox regulation of DNA repair in vivo? Free Radic. Biol. Med., 33: 875-885. https://doi.org/10.1016/S0891-5849(02)00882-1

Ma, Y., Ha, C.S., Hwang, W.S., Lee, H.J., Kim, G.C., Lee, K.W. and Song, K., 2014. Non-thermal atmospheric pressure plasma preferentially induces apoptosis in p53-mutated cancer cells by activating ROS stress-response pathways. PLoS One, 9: e91947. https://doi.org/10.1371/journal.pone.0091947

Mantovani, A., 2005. Cancer: Inflammation by remote control. Nature, 435: 752–753. https://doi.org/10.1038/435752a

Mantovani, A., Allavena, P., Sica, A. and Balkwill, F., 2008. Cancer related inflammation. Nature, 454: 436–444. https://doi.org/10.1038/nature07205

Martindale, J.L. and Holbrook, N.J., 2002. Cellular response to oxidative stress: Signaling for suicide and survival. J. Cell Physiol., 192: 1–15. https://doi.org/10.1002/jcp.10119

Medan, D., Wang, L., Toledo, D., Lu, B., Stehlik, C., Jiang, B.H., Shi, X. and Rojanasakul, Y., 2005. Regulation of Fas (CD95)-induced apoptotic and necrotic cell death by reactive oxygen species in macrophages. J. Cell Physiol., 203: 78–84. https://doi.org/10.1002/jcp.20201

Miguel, M.D. and Cordero, M.D., 2012. Oxidative therapy against cancer. InTech Open. https://doi.org/10.5772/33251

Misra, P. and Reddy, K., 2014. Peroxisome proliferator-activated receptor-a activation and excessenergy burning in hepatocarcinogenesis. Biochimie, 98: 63-74. https://doi.org/10.1016/j.biochi.2013.11.011

Murillo, H., Schmidt, L.J. and Tindall, D.J., 2001. Tyrphostin AG825 triggers p38 mitogen-activated protein kinase-dependent apoptosis in androgen-independent prostate cancer cells C4 and C4-2. Cancer Res., 61: 7408–7412.

Murphy, M.P., 2009. How mitochondria produce reactive oxygen species. Biochem. J., 417: 1–13. https://doi.org/10.1042/BJ20081386

Nagane, M., Levitzki, A., Gazit, A., Cavenee, W.K. and Huang, H.J., 1998. Drug resistance of human glioblastoma cells conferred by a tumorspecific mutant epidermal growth factor receptor through modulation of Bcl-XL and caspase-3-like proteases. Proc. natl. Acad. Sci. USA, 95: 5724–5729. https://doi.org/10.1073/pnas.95.10.5724

Okon, I.S. and Zou, M.H., 2015. Mitochondrial ROS and cancer drug resistance: Implications for therapy. Pharm. Res., 100: 170–174. https://doi.org/10.1016/j.phrs.2015.06.013

Ozben, T., 2007. Oxidative stress and apoptosis: impact on cancer therapy. J. Pharm. Sci., 96: 2181–2196. https://doi.org/10.1002/jps.20874

Pelicano, H., Carney, D. and Huang, P., 2004. Ros stress in cancer cells and therapeutic implications. Drug Resist. Updat., 7: 97-110. https://doi.org/10.1016/j.drup.2004.01.004

Pervaiz, S. and Clement, M.V., 2004. Tumor intracellular redox status and drug resistance-serendipity or a causal relationship? Curr. Pharm. Des., 10: 1969–1977. https://doi.org/10.2174/1381612043384411

Phillips, G.D.L., Fields, C.T., Li, G., Dowbenko, D., Schaefer, G., Miller, K., Andre, F., Burris III, H.A., Albain, K.S., Harbeck, N., Dieras, V., Crivellar, D., Fang, L., Guardino, E., Steven, R., Olsen, S.R., Crocker, L.M. and Sliwkowski, M.X., 2014. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: Critical role for neuregulin blockade in antitumor response to combination therapy. Clin. Cancer Res., 20: 278. https://doi.org/10.1158/1078-0432.CCR-13-0358

Poli, G., Leonarduzzi, G., Biasi, F. and Chiarpotto, E., 2004. Oxidative stress and cell signaling. Curr. Med. Chem., 11: 1163–1182. https://doi.org/10.2174/0929867043365323

Pouyssegur, J. and Mechta-Grigoriou, F., 2006. Redox regulation of the hypoxia-inducible factor. Biol. Chem., 387: 1337–1346. https://doi.org/10.1515/BC.2006.167

Pramanik, K.C. and Pandey, A., 2013. Critical role of oxidant and anti-oxidant in cancer. Mol. Biol., 2: 2. https://doi.org/10.4172/2168-9547.1000e110

Puntel, R.L., Roos, D.H., Grotto, D., Garcia, S.C., Nogueira, C.W. and Rocha, J.B., 2007. Antioxidant properties of Krebs cycle intermediates against malonate pro-oxidant activity in vitro: A comparative study using the colorimetric method and HPLC analysis to determine malondialdehyde in rat brain homogenates. Life Sci., 81: 51–62. https://doi.org/10.1016/j.lfs.2007.04.023

Qu, Y., Wang, J., Ray, P.S., Guo, H., Huang, J., Shin-Sim, M., Bukoye, B.A., Liu, B., Lee, A.V., Lin, X., Huang, P., Martens, J.W., Giuliano, A.E., Zhang, N., Cheng, N.H. and Cui, X., 2011. Thioredoxin- like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-kappa B signaling. J. Clin. Invest., 121: 212–225. https://doi.org/10.1172/JCI43144

Ralph, S.J., Rodriguez-Enriquez, S., Neuzil, J., Saavedra, E. and Moreno-Sanchez, R., 2010. The causes of cancer revisited: ‘‘mitochondrial malignancy’’ and ROS-induced oncogenic transformation—why mitochondria are targets for cancer therapy. Mol. Aspects Med., 31: 145–170. https://doi.org/10.1016/j.mam.2010.02.008

Ramsey, M.R. and Sharpless, N.E., 2006. ROS as a tumour suppressor? Nat. Cell Biol., 8: 1213–1215. https://doi.org/10.1038/ncb1106-1213

Reinehr, R., Becker, S., Eberle, A., Grether-Beck, S. and Haussinger, D., 2005. Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. J. biol. Chem., 280: 27179–27194. https://doi.org/10.1074/jbc.M414361200

Renschler, M.F., 2004. The emerging role of reactive oxygen species in cancer therapy. Eur. J. Cancer, 40: 1934–1940. https://doi.org/10.1016/j.ejca.2004.02.031

Retel, J., Hoebee, B., Braun, J.E., Lutgerink, J.T., van den Akker, E., Wanamarta, A.H., Joenje, H. and Lafleur, M.V., 1993. Mutational specificity of oxidative DNA damage. Mutat. Res., 299: 165-182. https://doi.org/10.1016/0165-1218(93)90094-T

Reuter, S., Gupta, S.C., Chaturvedi, M.M. and Aggarwal, B.B., 2010. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic. Biol. Med., 49: 1603–1616. https://doi.org/10.1016/j.freeradbiomed.2010.09.006

Rhee, S.G., 2006. Cell signaling. H2O2, a necessary evil for cell signaling. Science, 312: 1882–1883. https://doi.org/10.1126/science.1130481

Rodríguez-Hernández, A., Cordero, M.D., Salviati, L., Artuc, R., Pineda, M., Briones, P., Gómez Izquierdo, L., Cotán, D., Navas, P. and Sánchez-Alcázar, J.A., 2009. Coenzyme Q deficiency triggers mitochondria degradation by mitophagy. Autophagy, 5: 19-32. https://doi.org/10.4161/auto.5.1.7174

Ruiz-Ramos, R., Lopez-Carrillo, L., Rios-Perez, A.D., De Vizcaya- Ruiz, A. and Cebrian, M.E., 2009. Sodium arsenite induces ROS generation, DNA oxidative damage, HO-1 and c-Myc proteins, NF-kappaB activation and cell proliferation in human breast cancer MCF-7 cells. Mutat. Res., 674: 109–115. https://doi.org/10.1016/j.mrgentox.2008.09.021

Salman, K.A. and Ashraf, S., 2013. Reactive oxygen species: A link between chronic inflammation and cancer. Asian-Pacific J. mol. Biol. Biotechnol., 21: 42-49.

Sandhu, C. and Slingerland, J., 2000. Desregulación of the cell cycle in cancer. Cancer Detect. Prev., 24: 107-118.

Schafer, F.Q. and Buettner, G.R., 2001. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic. Biol. Med., 30: 1191–1212. https://doi.org/10.1016/S0891-5849(01)00480-4

Schetter, A.J., Heegaard, N.H. and Harris, C.C., 2010. Inflammation and cancer: Interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis, 31: 37–49. https://doi.org/10.1093/carcin/bgp272

Schumacker, P.T., 2006. Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell, 10: 175–176. https://doi.org/10.1016/j.ccr.2006.08.015

Seifried, H.E., Anderson, D.E., Fisher, E.I. and Milner, J.A., 2007. A review of the interaction among dietary antioxidants and reactive oxygen species. J. Nutr. Biochem., 18: 567–579. https://doi.org/10.1016/j.jnutbio.2006.10.007

Seo, Y.R., Kelley, M.R. and Smith, M.L., 2002. Selenomethionine regulation of p53 by a ref1-dependent redox mechanism. Proc. natl. Acad. Sci. USA, 99: 14548–14553. https://doi.org/10.1073/pnas.212319799

Simon, H.U., Haj-Yehia, A. and Levi-Schaffer, F., 2000. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis, 5: 415–418. https://doi.org/10.1023/A:1009616228304

Spitz, D.R., Sim, J.E., Ridnour, L.A., Galoforo, S.S. and Lee, Y.J., 2000. Glucose deprivation-induced oxidative stress in human tumor cells. A fundamental defect in metabolism? Annls. N.Y. Acad. Sci., 899: 349-362. https://doi.org/10.1111/j.1749-6632.2000.tb06199.x

Sternlicht, M.D. and Werb, Z., 2001. How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol., 17: 463–516. https://doi.org/10.1146/annurev.cellbio.17.1.463

Stojnev, S., Risti-Petrovi, A. and Jankovi-Velikovi, L., 2013. Reactive oxygen species, apoptosis and cancer. Vojnosanit Preg., l70: 675–678. https://doi.org/10.2298/VSP1307675S

Storz, P., 2006. Reactive oxygen species-mediated mitochondria-to-nucleus signaling: A key to aging and radical-caused diseases. Sci. STKE, 2006: re3. https://doi.org/10.1126/stke.3322006re3

Sugimura, T., 1998. Cancer prevention: Past, present, future. Mutat. Res., 402: 7-14. https://doi.org/10.1016/S0027-5107(97)00276-5

Sullivan, R. and Graham, C.H., 2008. Chemosensitization of cancer by nitric oxide. Curr. Pharm. Des., 14: 1113–1123. https://doi.org/10.2174/138161208784246225

Sundaresan, M., Yu, Z.X., Ferrans, V.J., Sulciner, D.J., Gutkind, J.S., Irani, K., Goldschmidt-Clermont, P.J. and Finkel, T., 1996. Regulation of reactive oxygen-species generation in fibroblasts by Rac1. Biochemistry, 318: 379-382. https://doi.org/10.1042/bj3180379

Szabo, C., Ischiropoulos, H. and Radi, R., 2007. Peroxynitrite: Biochemistry, pathophysiology and development of therapeutics. Nat. Rev. Drug Discov., 6: 662–680. https://doi.org/10.1038/nrd2222

Szatrowski, T.P. and Nathan, C.F., 1991. Production of large amounts ofhydrogen peroxide by human tumor cells. Cancer Res., 51: 794-798.

Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S., Tahara, H., Nakayama, K., Nakayama, K.I., Ide, T., Saya, H. and Hara, E., 2006. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat. Cell Biol., 8: 1291–1297. https://doi.org/10.1038/ncb1491

Tiligada, E., 2006. Chemotherapy: Induction of stress responses. Endocr. Relat. Cancer, 1: 115–124. https://doi.org/10.1677/erc.1.01272

Trachootham, D., Alexandre, J. and Huang, P., 2009. Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nat. Rev. Drug Discov., 8: 579–591. https://doi.org/10.1038/nrd2803

Tsai, C.M., Levitzki, A., Wu, L.H., Chang, K.T., Cheng, C.C., Gazit, A. and Perng, R.P., 1996. Enhancement of chemosensitivity by tyrphostin AG825 in high-p185(neu) expressing non-small cell lung cancer cells. Cancer Res., 56: 1068–1074.

Uchikura, K., Wada, T., Hoshino, S., Nagakawa, Y., Aiko, T., Bulkley, G.B., Klein, A.S. and Sun, Z., 2004. Lipopolysaccharides induced increases in Fas ligand expression by Kupffer cells via mechanisms dependent on reactive oxygen species. Am. J. Physiol. Gastrointest. Liver Physiol., 287: G620–G626. https://doi.org/10.1152/ajpgi.00314.2003

Ushio-Fukai, M. and Alexander, R.W., 2004. Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol. Cell. Biochem., 264: 85–97. https://doi.org/10.1023/B:MCBI.0000044378.09409.b5

Ushio-Fukai, M. and Nakamura, Y., 2008. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett., 266: 37–52. https://doi.org/10.1016/j.canlet.2008.02.044

Ushio-Fukai, M., 2006. Redox signaling in angiogenesis: Role of NADPH oxidase. Cardiovasc. Res., 71: 226–235. https://doi.org/10.1016/j.cardiores.2006.04.015

Valko, M., Izakovic, M., Mazur, M., Rhodes, C.J. and Telser, J., 2004. Role of oxygen radicals in DNA damage and cancer incidence. Mol. Cell. Biochem., 266: 37–56. https://doi.org/10.1023/B:MCBI.0000049134.69131.89

Valko, M., Rhodes, C.J., Moncol, J., Izakovic, M. and Mazura, M., 2006. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chemico-Biol. Interact., 160: 1–40. https://doi.org/10.1016/j.cbi.2005.12.009

Veal, E.A., Day, A.M. and Morgan, B.A., 2007. Hydrogen peroxide sensing and signaling. Mol. Cell, 26: 1–14. https://doi.org/10.1016/j.molcel.2007.03.016

Verstovsek, S., Kantarjian, H., Mesa, R.A., Pardanani, A.D., Cortes-Franco, J., Thomas, D.A., Estrov, Z., Fridman, J.S., Bradley, E.C., Erickson-Viitanen, S., Vaddi, K., Levy, R. and Tefferi, A., 2010. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. New Eng. J. Med., 363: 1117–1127. https://doi.org/10.1056/NEJMoa1002028

Wada, T. and Penninger, J.M., 2004. Mitogen-activated protein kinases in apoptosis regulation. Oncogene, 23: 2838-2849. https://doi.org/10.1038/sj.onc.1207556

Wang, J. and Yi, J., 2008. Cancer cell killing via ROS to increase or decrease, that is the question. Cancer Biol. Ther., 7: 1875–1884. https://doi.org/10.4161/cbt.7.12.7067

Wang, J.C., 2010. Good cells gone bad: The cellular origins of cancer. Trends Mol. Med., 16: 145–151. https://doi.org/10.1016/j.molmed.2010.01.001

Wang, X., Martindale, J.L., Liu, Y. and Holbrook, N.J., 1998. The cellular response to oxidative stress: influences of mitogen-activated protein kinase signaling pathways on cell survival. Biochem. J., 333: 291-300. https://doi.org/10.1042/bj3330291

Wang, X., Son, Y.O., Chang, Q., Sun, L., Hitron, J.A., Budhraja, A., Zhang, Z., Ke, Z., Chen, F., Luo, J. and Shi, X., 2011. NADPH oxidase activation is required in reactive oxygen species generation and cell transformation induced by hexavalent chromium. Toxicol. Sci., 123: 399–410. https://doi.org/10.1093/toxsci/kfr180

Wang, X., Zhang, J. and Xu, T., 2007. Cyclophosphamide as a potent inhibitor of tumor thioredoxin reductase in vivo. Toxicol. appl. Pharmacol., 218: 88–95. https://doi.org/10.1016/j.taap.2006.10.029

Wang, Y., 2001. The role and regulation of urokinase-type plasminogen activator receptor gene expression in cancer invasion and metastasis. Med. Res. Rev., 21: 146–170. https://doi.org/10.1002/1098-1128(200103)21:2<146::AID-MED1004>3.0.CO;2-B

Waris, G. and Ahsan, H., 2006. Reactive oxygen species: Role in the development of cancer and various chronic conditions. J. Carcinogenesis, 5: 14. https://doi.org/10.1186/1477-3163-5-14

Winterbourn, C.C., 2008. Reconciling the chemistry and biology of reactive oxygen species. Nat. Chem. Biol., 4: 278–286. https://doi.org/10.1038/nchembio.85

Wiseman, H. and Halliwell, B., 1996. Damage to DNA by reactive oxygen and nitrogen species: Role in inflammatory disease and progression to cancer. Biochem J., 313: 17-29. https://doi.org/10.1042/bj3130017

Wochna, A., Niemczyk, E., Kurono, C., Masaoka, M., Kedzior, J., Slominska, E., Lipinski, M. and Wakabayashi, T., 2007. A possible role of oxidative stress in the switch mechanism of the cell death mode from apoptosis to necrosis studies on rho cells. Mitochondrion, 7: 119–124. https://doi.org/10.1016/j.mito.2006.11.005

Wu, W.S., 2006. The signaling mechanism of ROS in tumor progression. Cancer Metast. Rev., 25: 695–705. https://doi.org/10.1007/s10555-006-9037-8

Yano, M., Ikea, M., Abe, K., Kawai, Y., Kuroki, M., Mori, K., Dansako, H., Ariumi, Y., Ohkoshi, S., Aoyagi, Y. and Kato, N., 2009. Oxidative stress induces anti-hepatitis C virus status via the activation of extracellular signal regulated kinase. Hepatology, 50: 556-564. https://doi.org/10.1002/hep.23026

Zhou, Y., Shu, F., Liang, X., Chang, H., Shi, L., Peng, X., Zhu, J. and Mi, M., 2014. Ampelopsin induces cell growth inhibition and apoptosis in breast cancer cells through ROS generation and endoplasmic reticulum stress pathway. PLoS One, 9: e89021. https://doi.org/10.1371/journal.pone.0089021

Zorov, D.B., Juhaszova, M. and Sollott, S.J., 2006. Mitochondrial ROS-induced ROS release: An update and review. Biochim. Biophys. Acta, 1757: 509-517. https://doi.org/10.1016/j.bbabio.2006.04.029

Zou, P., Zhang, J., Xia, Y., Kanchana, K., Guo, G., Chen, W., Huang, Y., Wang, Z., Yang, S. and Liang, G., 2015. ROS generation mediates the anti-cancer effects of WZ35 via activating JNK and ER stress apoptotic pathways in gastric cancer. Oncotarget, 6: 5860-5876. https://doi.org/10.18632/oncotarget.3333