The researchers found that different cancer-associated genes affect the heart in different ways — a sign that genetic information could one day guide heart-protective treatment decisions in cancer patients. The study is published in the journal Antioxidants. However, emerging research has suggested that heart problems can surface before cancer treatment or muscle wasting occur.

The Ohio State team noted that a study published recently in the Journal of the America Heart Association reported the detection of abnormalities in heart tissue and cardiac function in human cancer patients before cancer treatment had begun.

The scientists observed significantly lower ejection fraction and fractional shortening — similar to what was seen in mice with tumors — as well as an increase in heart rate in flies with tumors.

The researchers found a total-body increase in the rate of production as well as a higher total number of free radicals — also known as reactive oxygen species — in fruit flies with tumors compared to controls.

The rate of reactive oxygen species production was also significantly higher in mice with tumors compared to controls. She and Singh also emphasized that reactive oxygen species are just one identified mechanism of tumor-related heart damage, and that there is still a lot to learn about how antioxidants might fit into a treatment regimen.

Though this research zeroed in on one cancer-causing gene to study the mechanism of heart damage in fruit flies, the researchers initially tested the effects of several cancer-causing genes in the flies.

The heart function affected and the intensity of the effects on the heart varied, depending on the gene. Singh is collaborating with clinicians at Ohio State and other institutions to collect blood samples from cancer patients who have heart failure.

Second, we want to see what the message is and whether we can prescribe antioxidants. Additional co-authors include Priyanka Karekar, Haley Jensen, Kathryn Russart, Devasena Ponnalagu, Shridhar Sanghvi, Sakima Smith and Leah Pyter from Ohio State and Sarah Seeley from Ohio Northern University ONU.

The work was supported by Commonwealth Universal Research Enhancement Program grants, the W. Int J Radiat Biol , 85 12 Jian Liu K, Rosenberg GA: Matrix metalloproteinases and free radicals in cerebral ischemia.

Free Radical Biol Med , 39 1 Jomova K, Valko M: Importance of iron chelation in free radical-induced oxidative stress and human disease. Curr Pharm Des , 17 31 Jones DP, Carlson JL, Mody VC Jr, Cai J, Lynn MJ, Sternberg P Jr: Redox state of glutathione in human plasma.

Free Radical Biol Med , 28 4 J-w Z, Rubio V, Zheng S, Z-z S: Knockdown of OLA1, a regulator of oxidative stress response, inhibits motility and invasion of breast cancer cells.

Journal of Zhejiang University SCIENCE B , 10 11 Kempner ES: Direct effects of ionizing radiation on macromolecules. J Polym Sci B , 49 12 Kheradmand F, Werner E, Tremble P, Symons M, Werb Z: Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change.

Science , Kim J, Gherasim C, Banerjee R: Decyanation of vitamin B12 by a trafficking chaperone. Proc Natl Acad Sci , 38 Kim H-S, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, van der Meer R, Nguyen P, Savage J, Owens KM: SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress.

Cancer cell , 17 1 Klaunig JE, Kamendulis LM: The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol , Klaunig JE, Kamendulis LM, Hocevar BA: Oxidative stress and oxidative damage in carcinogenesis. Toxicologic pathology , 38 1 Kumar B, Koul S, Khandrika L, Meacham RB, Koul HK: Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype.

Cancer research , 68 6 Kumar A, Pant M, Singh H, Khandelwal S: Assessment of the redox profile and oxidative DNA damage 8-OHdG in squamous cell carcinoma of head and neck. J Cancer Res Ther , 8 2 Lee JJ, Lee JH, Ko YG, Hong SI, Lee JS: Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species.

Oncogene , 29 4 Leonardo CC, Pennypacker KR: Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury. J Neuroinflammation , 6: Differentiation , 70 2—3 Li H, Sekine M, Seng S, Avraham S, Avraham HK: BRCA1 Interacts with Smad3 and Regulates Smad3-Mediated TGF-b Signaling during Oxidative Stress Responses.

PloS one , 4 9 :e Li L, Ishdorj G, Gibson SB: Reactive oxygen species regulation of autophagy in cancer: Implications for cancer treatment. Free Radical Biol Med , 53 7 Luo J, Solimini NL, Elledge SJ: Principles of cancer therapy: oncogene and non-oncogene addiction.

Cell , 5 Mahelkova G, Korynta J, Moravova A, Novotna J, Vytasek R, Wilhelm J: Changes of extracellular matrix of rat cornea after exposure to hypoxia. Physiol Res , 57 1 Marnett LJ: Oxyradicals and DNA damage. Carcinogenesis , 21 3 Martínez Sarrasague M, Barrado DA, Zubillaga M, Hager A, De Paoli T, Boccio J: Conceptos actuales del metabolismo del glutatión Utilización de los isótopos estables para la evaluación de su homeostasis.

Acta bioquímica clínica latinoamericana , 40 1 Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen H-Y, Bray K, Reddy A, Bhanot G, Gelinas C: Autophagy suppresses tumorigenesis through elimination of p Meley D, Bauvy C, Houben-Weerts JH, Dubbelhuis PF, Helmond MT, Codogno P, Meijer AJ: AMP-activated protein kinase and the regulation of autophagic proteolysis.

J Biol Chem , 46 Mena S, Ortega A, Estrela JM: Oxidative stress in environmental-induced carcinogenesis. Mori K, Shibanuma M, Nose K: Invasive potential induced under long-term oxidative stress in mammary epithelial cells. Cancer research , 64 20 Muriel P: Role of free radicals in liver diseases.

Hepatology international , 3 4 Murley JS, Kataoka Y, Miller RC, Li JJ, Woloschak G, Grdina DJ: SOD2-mediated effects induced by WR and low-dose ionizing radiation on micronucleus formation in RKO human colon carcinoma cells.

Radiation research , 1 Nathan C: Nitric oxide as a secretory product of mammalian cells. FASEB J , 6 12 Nelson KK, Ranganathan AC, Mansouri J, Rodriguez AM, Providence KM, Rutter JL, Pumiglia K, Bennett JA, Melendez JA: Elevated Sod2 Activity Augments Matrix Metalloproteinase Expression Evidence for the Involvement of Endogenous Hydrogen Peroxide in Regulating Metastasis.

Clin Cancer Res , 9 1 Okezie I, Harparkash K, Haliwell B: Oxygen free radicals and human diseases. J Roy Soc Health , Oronsky BT, Knox SJ, Scicinski JJ: Is nitric oxide NO the last word in radiosensitization? A review. Translational Oncology , 5 2 Pande D, Negi R, Khanna S, Khanna R, Khanna HD: Vascular endothelial growth factor levels in relation to oxidative damage and antioxidant status in patients with breast cancer.

Journal of breast cancer , 14 3 Pande D, Negi R, Karki K, Khanna S, Khanna RS, Khanna HD: Oxidative damage markers as possible discriminatory biomarkers in breast carcinoma.

Transl Res , 6 Pani G, Galeotti T, Chiarugi P: Metastasis: cancer cell's escape from oxidative stress. Cancer Metastasis Rev , 29 2 Panis C, Herrera AC, Victorino VJ, Campos FC, Freitas LF, De Rossi T, Colado Simão AN, Cecchini AL, Cecchini R: Oxidative stress and hematological profiles of advanced breast cancer patients subjected to paclitaxel or doxorubicin chemotherapy.

Breast Cancer Res Treat , 1 Paquette B, Baptiste C, Therriault H, Arguin G, Plouffe B, Lemay R: In vitro irradiation of basement membrane enhances the invasiveness of breast cancer cells.

Brit J Cancer , 97 11 Pervin S, Tran L, Urman R, Braga M, Parveen M, Li S, Chaudhuri G, Singh R: Oxidative stress specifically downregulates survivin to promote breast tumour formation. Brit J Cancer , 4 Polidori MC, Stahl W, Eichler O, Niestroj I, Sies H: Profiles of antioxidants in human plasma.

Free Radical Biol Med , 30 5 Polyak K, Weinberg RA: Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer , 9 4 Pourahmad J, O'Brien PJ, Jokar F, Daraei B: Carcinogenic metal induced sites of reactive oxygen species formation in hepatocytes.

Toxicol In Vitro , 17 5—6 Prousek J: Fenton chemistry in biology and medicine. Pure Appl Chem , 79 12 Purdom S, Chen QM: Epidermal growth factor receptor-dependent and-independent pathways in hydrogen peroxide-induced mitogen-activated protein kinase activation in cardiomyocytes and heart fibroblasts.

J Pharmacol Exp Ther , 3 Quievryn G, Messer J, Zhitkovich A: Carcinogenic chromium VI induces cross-linking of vitamin C to DNA in vitro and in human lung A cells. Biochemistry , 41 9 Rahman MA, Senga T, Ito S, Hyodo T, Hasegawa H, Hamaguchi M: S-nitrosylation at cysteine of c-Src tyrosine kinase regulates nitric oxide-mediated cell invasion.

J Biol Chem , 6 Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF: Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S: Regulation of mammalian autophagy in physiology and pathophysiology.

Physiol Rev , 90 4 Reynolds M, Stoddard L, Bespalov I, Zhitkovich A: Ascorbate acts as a highly potent inducer of chromate mutagenesis and clastogenesis: linkage to DNA breaks in G2 phase by mismatch repair.

Nucleic Acids Res , 35 2 Ridnour LA, Thomas DD, Mancardi D, Espey MG, Miranda KM, Paolocci N, Feelisch M, Fukuto J, Wink DA: The chemistry of nitrosative stress induced by nitric oxide and reactive nitrogen oxide species.

Putting perspective on stressful biological situations. Biol Chem , 1 Roberts RA, Laskin DL, Smith CV, Robertson FM, Allen EM, Doorn JA, Slikker W: Nitrative and oxidative stress in toxicology and disease. Toxicological sciences , 1 Rosenberg GA: Matrix metalloproteinases in neuroinflammation.

Glia , 39 3 Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM: The antioxidant function of the p53 tumor suppressor. Nature medicine , 11 12 Free Radical Biol Med , 30 11 Schafer ZT, Grassian AR, Song L, Jiang Z, Gerhart-Hines Z, Irie HY, Gao S, Puigserver P, Brugge JS: Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment.

Scherz-Shouval R, Elazar Z: ROS, mitochondria and the regulation of autophagy. Trends in cell Biol , 17 9 Schetter AJ, Heegaard NH, Harris CC: Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis , 31 1 Schramek D, Kotsinas A, Meixner A, Wada T, Elling U, Pospisilik JA, Neely GG, Zwick R-H, Sigl V, Forni G: The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression.

Nature genetics , 43 3 Sethy-Coraci I, Crock LW, Silverstein SC: PAF-receptor antagonists, lovastatin, and the PTK inhibitor genistein inhibit H2O2 secretion by macrophages cultured on oxidized-LDL matrices. Journal of leukocyte biology , 78 5 Shen K, Ji L, Chen Y, Yu Q, Wang Z: Influence of glutathione levels and activity of glutathione-related enzymes in the brains of tumor-bearing mice.

Bioscience trends , 5 1 Cancer chemotherapy and pharmacology , 67 6 Singh S, Sreenath K, Pavithra L, Roy S, Chattopadhyay S: SMAR1 regulates free radical stress through modulation of AKR1a4 enzyme activity. Int J Biochem Cell Biol , 42 7 Skrzydlewska E, Sulkowski S, Koda M, Zalewski B, Kanczuga-Koda L, Sulkowska M: Lipid peroxidation and antioxidant status in colorectal cancer.

World J Gastroenterol , 11 3 Speisky H, Gómez M, Burgos-Bravo F, López-Alarcón C, Jullian C, Olea-Azar C, Aliaga ME: Generation of superoxide radicals by copper-glutathione complexes: Redox-consequences associated with their interaction with reduced glutathione.

Bioorg Med Chem , 17 5 Sung HJ, Ma W, P-y W, Hynes J, O'Riordan TC, Combs CA, McCoy JP, Bunz F, Kang J-G, Hwang PM: Mitochondrial respiration protects against oxygen-associated DNA damage. Nat Commun , 1: 5. Tao R, Coleman MC, Pennington JD, Ozden O, Park S-H, Jiang H, Kim H-S, Flynn CR, Hill S, Hayes McDonald W: Sirt3-mediated deacetylation of evolutionarily conserved lysine regulates MnSOD activity in response to stress.

Molecular cell , 40 6 Teixeira V, Valente H, Casal S, Marques F, Moreira P: Blood antioxidant and oxidative stress biomarkers acute responses to a m kayak sprint in elite male kayakers. J Sports Med physical fitness , 53 1 Ten Kate M, van der Wal J, Sluiter W, Hofland L, Jeekel J, Sonneveld P, van Eijck C: The role of superoxide anions in the development of distant tumour recurrence.

Brit J Cancer , 95 11 Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer , 2 6 Turi JL, Jaspers I, Dailey LA, Madden MC, Brighton LE, Carter JD, Nozik-Grayck E, Piantadosi CA, Ghio AJ: Oxidative stress activates anion exchange protein 2 and AP-1 in airway epithelial cells.

Am J Physiol Lung Cell Mol Physiol , 4 :LL Valko M, Rhodes C, Moncol J, Izakovic M, Mazur M: Free radicals, metals and antioxidants in oxidative stress-induced cancer.

Chemico-biological interactions , 1 Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J: Free radicals and antioxidants in normal physiological functions and human disease.

Int J Biochem Cell Biol , 39 1 Vera-Ramirez L, Sanchez-Rovira P, Ramirez-Tortosa MC, Ramirez-Tortosa CL, Granados-Principal S, Lorente JA, Quiles JL: Free radicals in breast carcinogenesis, breast cancer progression and cancer stem cells.

Biological bases to develop oxidative-based therapies. Crit Rev Oncol Hematol , 80 3 Vesper BJ, Elseth KM, Tarjan G, Haines GK III, Radosevich JA: Long-term adaptation of breast tumor cell lines to high concentrations of nitric oxide.

Tumor Biology , 31 4 Wang Y, Shang Y: Epigenetic control of epithelial-to-mesenchymal transition and cancer metastasis.

Exp Cell Res , 2 Weinberg F, Chandel NS: Reactive oxygen species-dependent signaling regulates cancer. Cellular and molecular life sciences , 66 23 Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, Howell A, Pavlides S, Tsirigos A, Ertel A, Pestell RG: Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue.

Cell Cycle , 10 23 Wolf FI, Torsello A, Tedesco B, Fasanella S, Boninsegna A, D'Ascenzo M, Grassi C, Azzena GB, Cittadini A: Hz extremely low frequency electromagnetic fields enhance cell proliferation and DNA damage: possible involvement of a redox mechanism.

Biochimica et Biophysica Acta BBA -Molecular Cell Research , 1 Wong K-K, Engelman JA, Cantley LC: Targeting the PI3K signaling pathway in cancer. Wood LD, Parsons DW, Sn J, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J: The genomic landscapes of human breast and colorectal cancers.

Woolston CM, Al-Attar A, Storr SJ, Ellis IO, Morgan DA, Martin SG: Redox protein expression predicts radiotherapeutic response in early-stage invasive breast cancer patients. Int J Radiat Oncol Biol Phys , 79 5 Wright DT, Cohn LA, Li H, Fischer B, Li CM, Adler KB: Interactions of oxygen radicals with airway epithelium.

Environmental health perspectives , Suppl 10 Xiao C, Sharp JA, Kawahara M, Davalos AR, Difilippantonio MJ, Hu Y, Li W, Cao L, Buetow K, Ried T: The XIST Noncoding RNA Functions Independently of BRCA1 in X Inactivation.

Zaremba T, Olinski R: Oxidative DNA damage—analysis and clinical significance. Postepy biochemistry , 56 2 Zhang HJ, Zhao W, Venkataraman S, Robbins ME, Buettner GR, Kregel KC, Oberley LW: Activation of matrix metalloproteinase-2 by overexpression of manganese superoxide dismutase in human breast cancer MCF-7 cells involves reactive oxygen species.

J Biol Chem , 23 Zhou L, Wang Y, Tian D, Yang J, Yang Y: Decreased levels of nitric oxide production and nitric oxide synthase-2 expression are associated with the development and metastasis of hepatocellular carcinoma.

Molecular medicine reports , 6 6 Ziech D, Franco R, Georgakilas AG, Georgakila S, Malamou-Mitsi V, Schoneveld O, Pappa A, Panayiotidis MI: The role of reactive oxygen species and oxidative stress in environmental carcinogenesis and biomarker development.

Chemico-biological interactions , 2 Z-y L, Yang Y, Ming M, Liu B: Mitochondrial ROS generation for regulation of autophagic pathways in cancer. Biochem Biophys Res Commun , 1 Download references. This study was supported by the Fondo de Investigación Sanitaria PI to M.

Artacho-Cordón is supported by the Spanish Ministry of Science and Education AP A grant from the Fundación Benéfica San Francisco Javier y Santa Cándida, University of Granada to S. Ríos-Arrabal greatly aided this work. This research was also funded by the Unidad de Apoyo a la Investigación of San Cecilio University Hospital, Granada.

The authors thank Glenn Harding for improving the English style of the manuscript. It has been confirmed that these organelles are the principal intracellular source of ROS production in most tissues.

Studies have shown that under physiological condition, complex II respiratory chain could also be a main regulator of ROS generation from mitochondria [ 13 ]. In eukaryotic cells, the mitochondrion is an important organelle that plays a main role in several critical processes.

The important role of mitochondria is mentioned in the physiology of cancer, such as in energy metabolism and cell cycle regulation. There is powerful documentary evidence to support the rationale for the expansion of anticancer strategies based on mitochondrial targets.

This organelle is recognizing to play an important role in the apoptosis mechanism and initiate cell death through various mechanisms that comprise disrupting electron transport and energy metabolism in the respiratory chain, releasing agents or proteins such as cytochrome c that mediate apoptosis signaling, and changing the cellular redox status by ROS generation.

The therapeutic targeting of cancer cells based on mitochondria have often depended on the intrinsic various differences between mitochondria in normal and cancer cells, which allow for better options, manipulation different pathways, and destruction of these cancer cells.

These differences are including bioenergetics change, disturbance of the mitochondrial DNA mtDNA , and morphological and physiological changes in the cancer cell Table 1. The mtDNA is one main target of ROS and the lack of sufficient protective histones surrounding the mtDNA in cancer cells makes the mtDNA more easily tending to ROS-caused DNA damage.

In addition, various researches have shown that the mitochondria were different in cancer cells than in normal cells, such as grow faster, fewer and smaller, and also had the morphological transformed [ 13 ]. Some differences between cancer and normal cells such as bioenergetics process, MMP and ROS level, and morphological and physiological differences.

Today, several mitochondria targeted strategies for cancer therapy have been focused on the development of agents that manage increased the ROS generation in mitochondria from the cancer cells without effect on the normal cells. It has been shown that ROS generation in the mitochondria is evaluated through the rates of both mitochondria ROS mtROS disposal and production, and ROS levels in mitochondria are regulated by several agents, including mitochondria O 2 levels, mitochondrial membrane potential MMP or Δψm , the metabolic condition of mitochondria, and other factors Figure 4.

A number of recent researches reveal the fact that mtROS at low to high levels act as several functions. That is it at low levels, involved in the hypoxia adaptation process, at moderate levels, involved in controlling inflammatory response, and at high level involved in regulating apoptosis signaling.

Adjustment of mitochondria ROS mtROS generation. Several agents such as MMP, the metabolic state of mitochondrial, O 2 level and STAT3 adjust the generation of mtROS. As mentioned in the previous section, the increase of ROS level of intracellular by sever agents through activating signaling pathways in cancer cells represents that these cells are more vulnerable than normal cells to ROS-caused cell death.

The results of the studies suggest that ROS such as H 2 O 2 could affect the extrinsic apoptosis pathway through changing the intracellular space. The up-regulation of receptor shows in various systems with increase ROS by exogenous ROS and ROS causing agents.

It has also been found to sensitize cancer cells, but not normal cells to TRAIL-caused apoptosis. Adenine nucleotide translocator ANT , as an inner mitochondrial protein, is also a target of ROS regulation by integrity of its redox-sensitive cysteines, supplying an extra mechanism by which drug-caused ROS generation may activate mitochondrial apoptosis signaling.

On the other hand, ROS also could regulate protein complexes inner place the mitochondrial electron transport chain mETC , activate caspases-3 and initiate apoptosis signaling. Today, agents that are used in the treatment of cancer through the mechanism of ROS generation are known as an important drug class.

Some studies have shown that several mitochondria-targeted drugs have potency useful in selective cancer cell killing and no effect on normal cells in pre-clinical and clinical testing, such as ROS regulators.

It has been shown that cancer cells in comparison with normal cells are more vulnerable to irreversible damage induced by stress oxidative and subsequent apoptosis. Researchers in previous studies have been used of the differences between the mitochondria between cancer and normal cells as a means to kill cancer cells by anti-cancer drugs.

Developing cancer therapies based on increasing further the high ROS level in cancer cells to a toxic level by the several mechanisms such as triggering ROS accumulation directly and inhibiting the antioxidant systems display powerful phenomenon of selectively killing cancer cells [ 6 ].

A number of drugs class have been recognized as increasing ROS production. It is well documented that some of chemotherapeutic agents can induce ROS generation through mitochondrial respiratory chain complexes in patients during cancer therapy.

These compounds can be separated into various categories such as alkylating agents, anthracycline antibiotics, platinum compounds, mitotic inhibitors, antimetabolites, biological response modifiers, and hormone therapies.

Arsenic trioxide ATO is used in the treatment of acute promyelocytic leukemia APL. It was reported that ATO induces apoptosis signaling in several cancer cells such as lung, leukemia, and myeloma cancer through the induction of ROS. The mechanism by which ATO cause increased ROS generation is not completely well known.

The most recent investigations indicated that ATO can impair the function of respiratory chain in the mitochondria, leading to increased generation of superoxide, likely by causing leakage of electrons from the mitochondrial respiratory chain complexes Figure 5.

On the other hand, ATO could be used in mixture with several anticancer drugs, which play a role through increasing ROS production. Mechanism of ROS generation and apoptosis induction by the ATO, doxorubicin, daunorubicin and bleomycin anthracycline antibiotics and cisplatin.

These drugs, leading to increased generation of ROS, likely by causing leakage of electrons from the mitochondrial respiratory chain complexes. The doxorubicin, daunorubicin, and bleomycin are an anthracycline antibiotics, cisplatin is a platinum compound, and amitriptyline as a tricyclic antidepressant are used in the treatment of several types of cancer.

The mechanism of doxorubicin bleomycin, cisplatin, and amitriptyline in the ROS production is the same of ATO. These drugs with impair the function of respiratory chain in the mitochondria, leading to increase generation of superoxide. These compounds due to this mechanism ROS generation are used for the treatment of several types of cancers Figure 5.

Studies have shown that other drugs such as dequalinium chloride preclinical and metformin preclinical and clinical, Phase I through inhibition of mitochondrial complex 1 have the ability to produce ROS.

VDACs, also known as mitochondrial porins, show high similarity between some animals especially mice and humans. VDAC play an important role in the cell, such as regulating mitochondrial shape and structural changes, regulating apoptosis signaling, regulating ATP and calcium transport. Several studies have demonstrated the role of VDAC in the regulation of apoptosis signaling and VDAC is being studied as a cancer-specific target.

As has been mentioned, these drugs promote ROS production through the disturbance of VDAC and cause non-apoptotic form of cell death in KRAS. Several studies have shown that some drugs and agents including, paclitaxel taxol , ionizing radiation, niclosamide, AGX, AG with effect on NOX induces ROS generation.

The recent results from both in vitro and in vivo studies have shown that this drug causes the translocation of Rac1, which favorably regulates the activity of NOX, thereby furthering ROS H 2 O 2 production.

It was reported that taxol can raise the levels of ROS in the extracellular and subsequently induced cancer cell death resulting in the release of cytochrome c from the mitochondria.

P53 act as a transcription factor to regulate the expression of many pro-oxidant genes. The 5-fluorouracil 5-FU is an antimetabolites and pyrimidine analog. It is used for therapies for several types of cancers, such as gastrointestinal, colon, rectal, and head and neck cancer, through inducing intracellular increase in superoxide.

The mechanism by which 5-FU cause increased ROS generation from mitochondria is through a pdependent pathway [ 4 ].

The two pathways GSH through enzymes such as GPX and GST and catalase can act directly on scavenging ROS in cells. For that reason, oxidative stress can be promoted with methods based on the loss of the reduced GSH storage and other antioxidant sources. A number of drugs class have been recognized as increasing oxidative stress process and ROS generation through targeting antioxidant system [ 4 , 5 ].

These drugs are, including buthionine sulfoximine BSO , imexon, phenylethyl isothiocyanate, mangafodipir, 2-methoxyestradiol, tetrathiomolybdate ATN , and auranofin, used in the treatment of various types of cancer.

For example, BSO through inhibition of the antioxidant system especially GSH in cancer cells such as ovarian and breast cancers can induce an accumulation of ROS due to the high basal ROS output in ovarian and breast cancers, and initiate cell death [ 4 , 5 ].

Other studies have shown that imexon through decrease GSH pool and subsequently increase the production of ROS and decrease mitochondria function was induced apoptosis.

Other studies have shown that some other drugs, including ascorbic acid and diethylmaleate are able effects on GSH GSH depletion. One the other hand, mercaptosuccinic acid, aminotriazol, and 2-Methoxyoestradiol were able to inhibit of GPx, catalase, and SOD, respectively, and thereby increase ROS production [ 7 ].

Cancer is a multistage disease including initiation, promotion, and progression. The increased ROS causes DNA damage, which may lead to DNA damage or gene mutation, resulting in the progression of cancer.

Increased generation of ROS and an altered redox status have observed in cancer cells, and investigations suggest that this biochemical property of cancer cells can be exploited for cancer therapy.

For treatment of cancer, since high levels of ROS can induce cell death, treatment of radiation, chemotherapy, and molecule compounds all can increase the level of intracellular ROS to induce cancer cell death and apoptosis.

The increased intracellular ROS levels could make cancer cells more vulnerable than normal cells to oxidative stress-induced cell death. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Edited by Rizwan Ahmad. Open access peer-reviewed chapter Role of Oxygen Free Radicals in Cancer Development and Treatment Written By Jalal Pourahmad, Ahmad Salimi and Enaytollah Seydi.

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Impact of this chapter. Abstract It is well known that species derived from oxygen are cytotoxic and are involved in the etiology of cancer. Keywords cancer reactive oxygen species oxidation therapy mitochondria.

pourahmadjaktaji utoronto. Mechanisms of free radical-induced DNA base modification and mutagenesis It has been appraised that in one human cell is exposed to nearly 10 5 oxidative hits such as hydroxyl radical and other such species in a day.

Role of ROS in genotoxicity and DNA damage ROS-caused DNA lesion may be characterized both structurally and chemically and displays a typical schema of modifications. Lipid peroxidation and DNA damage While major consideration has centralized on direct DNA lesion by oxygen free radicals because of the genetic outcomes of such lesion, reactive radical species may also induce damage to other cellular members.

Functions of ROS in the cancer cells. Antioxidant and oxidation pathways regulate ROS generation. NRF2 nuclear factor, erythroid-derived 2, like 2 NRF2 is an important regulator of the antioxidant system and cellular stress responses in the several cancers.

FOXO Forkhead box O and p53 FOXO, as a transcription factors, are involved in different signaling pathways and play key roles in some physiological and pathological processes such as cancer. Hypoxia and hypoglycemia Hypoxic conditions caused by the imbalance between intake and oxygen consumption [ 4 ].

Mitochondria In recent decades, several studies have shown that mitochondria organelle plays an important role in human health and disease. Cancer cells Normal cell Bioenergetics process Aerobic glycolysis condition "Warburg Effect" Aerobic condition Mitochondrial DNA mtDNA mtDNA is mutated mtDNA is normal Morphological and physiological differences shape and count Size and shape: smaller Size and shape: larger MMP level Higher ~60 mV Lower ROS level Higher Lower Intracellular pH Acidic No acidic Metabolic rates Higher Lower.

Table 1. Targeting mitochondrial respiratory chain Arsenic trioxide ATO is used in the treatment of acute promyelocytic leukemia APL. Targeting VDACs VDACs, also known as mitochondrial porins, show high similarity between some animals especially mice and humans. Targeting NOX Several studies have shown that some drugs and agents including, paclitaxel taxol , ionizing radiation, niclosamide, AGX, AG with effect on NOX induces ROS generation.

Targeting p53 P53 act as a transcription factor to regulate the expression of many pro-oxidant genes. References 1. Dizdaroglu M, Jaruga P, Birincioglu M, Rodriguez H. Free radical-induced damage to DNA: mechanisms and measurement 1, 2.

Free Radical Biology and Medicine. Waris G, Ahsan H. Reactive oxygen species: role in the development of cancer and various chronic conditions. Journal of Carcinogenesis.

Marnett LJ.

Oxidative stress is a serious health concern. It damages fatty tissue, DNA and proteins that the body needs to support essential, everyday processes. As the damage compounds, it can negatively impact your immune system.

Scientists believe it can event contribute to the development of serious diseases including diabetes, heart disease and cancer.

As free radicals build up and create progressively more oxidative stress, they do major damage to genes in our DNA. Over time, the damage can cause DNA to produce ineffective proteins, which affects DNA integrity. When DNA suffers, mutations occur.

The most common form of mutation occurs in genes known as tumor suppressor genes: the genes that function to repair cell damage and prevent cellular death.

A series of these mutations in the tumor suppressor genes and other genes are usually responsible for the formation of cancer cells. These are the cells that multiply into a malignant tumor. Fruits and vegetables! Consider having one vegetarian day per week or even going completely vegetarian.

Make your goal servings of fruits and vegetables per day. If you are unsure what a serving is, check out our article Confused About the Serving Sizes of Vegetables? Have you increased antioxidants in your diet? Maurer Foundation. July 11, Read More About the Author April Zubko Categories: Breast Cancer Prevention 0 comments.

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The American Journal of Clinical Nutrition. Lignitto L, LeBoeuf SE, Hamer H, et al. Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1.

doi: By Lynne Eldridge, MD Lynne Eldrige, MD, is a lung cancer physician, patient advocate, and award-winning author of "Avoiding Cancer One Day at a Time.

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Develop and improve services. Use limited data to select content. List of Partners vendors. By Lynne Eldridge, MD. Medically reviewed by Doru Paul, MD. Table of Contents View All. Table of Contents. What Are Free Radicals?

Causes and Sources. Free Radicals and Cancer. Reducing Free Radicals. Free Radicals and Oxidized Cholesterol in Your Body. How Free Radicals and Carcinogens Are Linked.

The Free Radical Theory of Aging There are several theories about why our bodies age and free radicals are a key player in many of them. Free Radicals and Aging. Do Free Radicals Cause Cancer Cells to Form? Anthocyanins and Free Radicals.

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Harman, and J. Miguel, eds. Oxygen radicals: A commonsense look at their nature and medical importance. Free radicals and metal ions in health and disease.

Halliwell and J. Oxygen toxicity, oxygen radicals, transition metals, and disease. Halliwell, and J. Free Radicals in Biology and Medicine. Clarendon Press, Oxford, The importance of free radicals and catalytic metal ions in human diseases. Aspects Med.

Oxygen radicals and the nervous system. Trends in Neurosci. Halliwell, J. Gutteridge, and D. Metal ions and oxygen radical reactions in human inflammatory joint disease. Royal Soc. B, — Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts. Iron and free radical reactions: two aspects of antioxidant protection.

TIBS 11, — The aging process. USA 78, — Free radicals and the origination, evolution, and present status of the free radical theory of aging. In Free Radicals in Molecular Biology , Ageing , and Disease , D. Armstrong, R. Sohal, R. Cutler, and T. Slater, eds.

Age 7, — Free radical theory of aging: Role of free radicals in the origination and evolution of life, aging, and disease processes. In Free Radicals, Ageing, and Degenerative Diseases, J.

Theories of biological aging. Micronutrients and cancer prevention. Chemical carcinogens in tobacco. In Cancer Risks , P. Bannasch, ed.

The ageing process is a key problem in biomedical research. Lancet ii , — Hughes, F. McDermott, A. Polglase, W. Johnson, and E. Large bowel cancer-the next move? Australia 1, 36—37 Brave New World. Chatto and Windus, London, Selenium inhibition of chemical carcinogenesis.

Kensler, and M. Role of oxygen radicals in tumour promotion. Germanium Ge : Homeostatic normalizer and immunostimulant. A review of its preventive and therapeutic efficacy.

Lathia, A. Braasch, and V. Inhibitory effects of vitamin C and E on in vitro formation of N-nitrosamine under physiological conditions. Loeb, V. Emster, K. Wamer, J. Abbots, and J. Smoking and lung cancer: An overview.

Marcus, N. Ibrahim, and M. Age-related decline in the biosynthesis of mitochondrial inner membrane proteins. Oxygen free radicals linked to many diseases.

Massie, V. Aiello, and T. Dietary vitamin C improves the survival of mice. Gerontology 30, — Oxygen-derived free radicals in postischemic tissue injury. Miller, and J. Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules.

Cancer 47, — Miguel, and J. Muir, and D. The world cancer burden: prevent or perish. Naqui, and B. Reactive oxygen intermediates in biochemistry. Oberley, and T. Free radicals, cancer, and aging. In Free Radicals , Ageing and Degenerative Diseases , J.

Oberley, T. Oberley, and G. Cell differentiation, aging, and cancer. The possible roles of superoxide and superoxide dis-mutases. Hypotheses 6, — Oliver, R. Fulks, R. Levine, L. Fucci, A.

Rivett, J. Roseman, and E. Oxidative inactivation of key metabolic enzymes. In Molecular Basis of Ageing , A. Ono, and S. Unique increase of superoxide dismutase level in brains of long living mammals. Evolution and the need for ascorbic acid.

USA 67, — How to Live Longer and Feel Better. Avon Books, New York, Peto, R. Doll, J. Buckley, and M. Can dietary beta-carotene materially reduce human cancer rates? Nature — Fundamentals of Oncology.

Marcel Dekker, New York, Proctor, and E. Free radicals and disease in man. NMR 16, — Cancer and free radicals.

Oxyradicals and related species: Their formation, lifetimes, and reactions. The New Zealand selenium experience. The alteration of enzymes in aging animals.

Salonen, G. Alfthan, J. Huttunen, and P. Association between serum selenium and the risk of cancer. Salonen, R. Lappetelainen, P. Maenpaa, G. Alfthan, and P. Risk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data.

Nutrition and Cancer , Plenum, New York, In Biochemistry of the Essential Ultratrace Elements , E. Frieden, ed. Shankel, P. Hartman, T. Kada, and A. Synopsis of the first international conference on mutagenesis and anticarcinogenesis.

Hypoxia, on the one hand, as a ROS inducer, can also directly induce the raised expression of oncogenes such as MYC and RAS through HIF-2α. On the other hand, MYC increases mitochondrial biogenesis, which adds to the raised ROS generation under hypoxic conditions and the raised mitochondrial ROS generation elevate the oxidative stress process [ 12 ].

It has been suggested that RAS, p53, and c-MYC through the mitochondria to regulate ROS generation, thereby affecting apoptosis. RAS in K-Ras-transformed fibroblast cell under the condition that glucose deprivation induces apoptosis through changes in mitochondrial complex gene expression.

It has also been reported that RAS in p66SHC overexpression condition in the transformed cells increase ROS generation through mitochondria and p53, MPTP opening and mitochondrial swelling could induce apoptosis Figure 3 [ 12 ]. In recent decades, several studies have shown that mitochondria organelle plays an important role in human health and disease.

These studies led to the emergence of a new field of study named "mitochondrial medicine. It has been confirmed that these organelles are the principal intracellular source of ROS production in most tissues.

Studies have shown that under physiological condition, complex II respiratory chain could also be a main regulator of ROS generation from mitochondria [ 13 ]. In eukaryotic cells, the mitochondrion is an important organelle that plays a main role in several critical processes.

The important role of mitochondria is mentioned in the physiology of cancer, such as in energy metabolism and cell cycle regulation. There is powerful documentary evidence to support the rationale for the expansion of anticancer strategies based on mitochondrial targets.

This organelle is recognizing to play an important role in the apoptosis mechanism and initiate cell death through various mechanisms that comprise disrupting electron transport and energy metabolism in the respiratory chain, releasing agents or proteins such as cytochrome c that mediate apoptosis signaling, and changing the cellular redox status by ROS generation.

The therapeutic targeting of cancer cells based on mitochondria have often depended on the intrinsic various differences between mitochondria in normal and cancer cells, which allow for better options, manipulation different pathways, and destruction of these cancer cells.

These differences are including bioenergetics change, disturbance of the mitochondrial DNA mtDNA , and morphological and physiological changes in the cancer cell Table 1. The mtDNA is one main target of ROS and the lack of sufficient protective histones surrounding the mtDNA in cancer cells makes the mtDNA more easily tending to ROS-caused DNA damage.

In addition, various researches have shown that the mitochondria were different in cancer cells than in normal cells, such as grow faster, fewer and smaller, and also had the morphological transformed [ 13 ]. Some differences between cancer and normal cells such as bioenergetics process, MMP and ROS level, and morphological and physiological differences.

Today, several mitochondria targeted strategies for cancer therapy have been focused on the development of agents that manage increased the ROS generation in mitochondria from the cancer cells without effect on the normal cells.

It has been shown that ROS generation in the mitochondria is evaluated through the rates of both mitochondria ROS mtROS disposal and production, and ROS levels in mitochondria are regulated by several agents, including mitochondria O 2 levels, mitochondrial membrane potential MMP or Δψm , the metabolic condition of mitochondria, and other factors Figure 4.

A number of recent researches reveal the fact that mtROS at low to high levels act as several functions. That is it at low levels, involved in the hypoxia adaptation process, at moderate levels, involved in controlling inflammatory response, and at high level involved in regulating apoptosis signaling.

Adjustment of mitochondria ROS mtROS generation. Several agents such as MMP, the metabolic state of mitochondrial, O 2 level and STAT3 adjust the generation of mtROS. As mentioned in the previous section, the increase of ROS level of intracellular by sever agents through activating signaling pathways in cancer cells represents that these cells are more vulnerable than normal cells to ROS-caused cell death.

The results of the studies suggest that ROS such as H 2 O 2 could affect the extrinsic apoptosis pathway through changing the intracellular space. The up-regulation of receptor shows in various systems with increase ROS by exogenous ROS and ROS causing agents.

It has also been found to sensitize cancer cells, but not normal cells to TRAIL-caused apoptosis. Adenine nucleotide translocator ANT , as an inner mitochondrial protein, is also a target of ROS regulation by integrity of its redox-sensitive cysteines, supplying an extra mechanism by which drug-caused ROS generation may activate mitochondrial apoptosis signaling.

On the other hand, ROS also could regulate protein complexes inner place the mitochondrial electron transport chain mETC , activate caspases-3 and initiate apoptosis signaling. Today, agents that are used in the treatment of cancer through the mechanism of ROS generation are known as an important drug class.

Some studies have shown that several mitochondria-targeted drugs have potency useful in selective cancer cell killing and no effect on normal cells in pre-clinical and clinical testing, such as ROS regulators.

It has been shown that cancer cells in comparison with normal cells are more vulnerable to irreversible damage induced by stress oxidative and subsequent apoptosis.

Researchers in previous studies have been used of the differences between the mitochondria between cancer and normal cells as a means to kill cancer cells by anti-cancer drugs.

Developing cancer therapies based on increasing further the high ROS level in cancer cells to a toxic level by the several mechanisms such as triggering ROS accumulation directly and inhibiting the antioxidant systems display powerful phenomenon of selectively killing cancer cells [ 6 ].

A number of drugs class have been recognized as increasing ROS production. It is well documented that some of chemotherapeutic agents can induce ROS generation through mitochondrial respiratory chain complexes in patients during cancer therapy. These compounds can be separated into various categories such as alkylating agents, anthracycline antibiotics, platinum compounds, mitotic inhibitors, antimetabolites, biological response modifiers, and hormone therapies.

Arsenic trioxide ATO is used in the treatment of acute promyelocytic leukemia APL. It was reported that ATO induces apoptosis signaling in several cancer cells such as lung, leukemia, and myeloma cancer through the induction of ROS.

The mechanism by which ATO cause increased ROS generation is not completely well known. The most recent investigations indicated that ATO can impair the function of respiratory chain in the mitochondria, leading to increased generation of superoxide, likely by causing leakage of electrons from the mitochondrial respiratory chain complexes Figure 5.

On the other hand, ATO could be used in mixture with several anticancer drugs, which play a role through increasing ROS production. Mechanism of ROS generation and apoptosis induction by the ATO, doxorubicin, daunorubicin and bleomycin anthracycline antibiotics and cisplatin.

These drugs, leading to increased generation of ROS, likely by causing leakage of electrons from the mitochondrial respiratory chain complexes. The doxorubicin, daunorubicin, and bleomycin are an anthracycline antibiotics, cisplatin is a platinum compound, and amitriptyline as a tricyclic antidepressant are used in the treatment of several types of cancer.

The mechanism of doxorubicin bleomycin, cisplatin, and amitriptyline in the ROS production is the same of ATO. These drugs with impair the function of respiratory chain in the mitochondria, leading to increase generation of superoxide. These compounds due to this mechanism ROS generation are used for the treatment of several types of cancers Figure 5.

Studies have shown that other drugs such as dequalinium chloride preclinical and metformin preclinical and clinical, Phase I through inhibition of mitochondrial complex 1 have the ability to produce ROS. VDACs, also known as mitochondrial porins, show high similarity between some animals especially mice and humans.

VDAC play an important role in the cell, such as regulating mitochondrial shape and structural changes, regulating apoptosis signaling, regulating ATP and calcium transport. Several studies have demonstrated the role of VDAC in the regulation of apoptosis signaling and VDAC is being studied as a cancer-specific target.

As has been mentioned, these drugs promote ROS production through the disturbance of VDAC and cause non-apoptotic form of cell death in KRAS.

Several studies have shown that some drugs and agents including, paclitaxel taxol , ionizing radiation, niclosamide, AGX, AG with effect on NOX induces ROS generation. The recent results from both in vitro and in vivo studies have shown that this drug causes the translocation of Rac1, which favorably regulates the activity of NOX, thereby furthering ROS H 2 O 2 production.

It was reported that taxol can raise the levels of ROS in the extracellular and subsequently induced cancer cell death resulting in the release of cytochrome c from the mitochondria. P53 act as a transcription factor to regulate the expression of many pro-oxidant genes. The 5-fluorouracil 5-FU is an antimetabolites and pyrimidine analog.

It is used for therapies for several types of cancers, such as gastrointestinal, colon, rectal, and head and neck cancer, through inducing intracellular increase in superoxide. The mechanism by which 5-FU cause increased ROS generation from mitochondria is through a pdependent pathway [ 4 ].

The two pathways GSH through enzymes such as GPX and GST and catalase can act directly on scavenging ROS in cells. For that reason, oxidative stress can be promoted with methods based on the loss of the reduced GSH storage and other antioxidant sources. A number of drugs class have been recognized as increasing oxidative stress process and ROS generation through targeting antioxidant system [ 4 , 5 ].

These drugs are, including buthionine sulfoximine BSO , imexon, phenylethyl isothiocyanate, mangafodipir, 2-methoxyestradiol, tetrathiomolybdate ATN , and auranofin, used in the treatment of various types of cancer.

For example, BSO through inhibition of the antioxidant system especially GSH in cancer cells such as ovarian and breast cancers can induce an accumulation of ROS due to the high basal ROS output in ovarian and breast cancers, and initiate cell death [ 4 , 5 ]. Other studies have shown that imexon through decrease GSH pool and subsequently increase the production of ROS and decrease mitochondria function was induced apoptosis.

Other studies have shown that some other drugs, including ascorbic acid and diethylmaleate are able effects on GSH GSH depletion.

One the other hand, mercaptosuccinic acid, aminotriazol, and 2-Methoxyoestradiol were able to inhibit of GPx, catalase, and SOD, respectively, and thereby increase ROS production [ 7 ].

Cancer is a multistage disease including initiation, promotion, and progression. The increased ROS causes DNA damage, which may lead to DNA damage or gene mutation, resulting in the progression of cancer.

Increased generation of ROS and an altered redox status have observed in cancer cells, and investigations suggest that this biochemical property of cancer cells can be exploited for cancer therapy. For treatment of cancer, since high levels of ROS can induce cell death, treatment of radiation, chemotherapy, and molecule compounds all can increase the level of intracellular ROS to induce cancer cell death and apoptosis.

The increased intracellular ROS levels could make cancer cells more vulnerable than normal cells to oxidative stress-induced cell death. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.

Edited by Rizwan Ahmad. Open access peer-reviewed chapter Role of Oxygen Free Radicals in Cancer Development and Treatment Written By Jalal Pourahmad, Ahmad Salimi and Enaytollah Seydi. DOWNLOAD FOR FREE Share Cite Cite this chapter There are two ways to cite this chapter:.

Choose citation style Select style Vancouver APA Harvard IEEE MLA Chicago Copy to clipboard Get citation. Choose citation style Select format Bibtex RIS Download citation. IntechOpen Free Radicals and Diseases Edited by Rizwan Ahmad. From the Edited Volume Free Radicals and Diseases Edited by Rizwan Ahmad Book Details Order Print.

Chapter metrics overview 3, Chapter Downloads View Full Metrics. Impact of this chapter. Abstract It is well known that species derived from oxygen are cytotoxic and are involved in the etiology of cancer.

Keywords cancer reactive oxygen species oxidation therapy mitochondria. pourahmadjaktaji utoronto. Mechanisms of free radical-induced DNA base modification and mutagenesis It has been appraised that in one human cell is exposed to nearly 10 5 oxidative hits such as hydroxyl radical and other such species in a day.

Role of ROS in genotoxicity and DNA damage ROS-caused DNA lesion may be characterized both structurally and chemically and displays a typical schema of modifications.

Lipid peroxidation and DNA damage While major consideration has centralized on direct DNA lesion by oxygen free radicals because of the genetic outcomes of such lesion, reactive radical species may also induce damage to other cellular members.

Functions of ROS in the cancer cells. Antioxidant and oxidation pathways regulate ROS generation. NRF2 nuclear factor, erythroid-derived 2, like 2 NRF2 is an important regulator of the antioxidant system and cellular stress responses in the several cancers.

FOXO Forkhead box O and p53 FOXO, as a transcription factors, are involved in different signaling pathways and play key roles in some physiological and pathological processes such as cancer. Hypoxia and hypoglycemia Hypoxic conditions caused by the imbalance between intake and oxygen consumption [ 4 ].

Mitochondria In recent decades, several studies have shown that mitochondria organelle plays an important role in human health and disease. Cancer cells Normal cell Bioenergetics process Aerobic glycolysis condition "Warburg Effect" Aerobic condition Mitochondrial DNA mtDNA mtDNA is mutated mtDNA is normal Morphological and physiological differences shape and count Size and shape: smaller Size and shape: larger MMP level Higher ~60 mV Lower ROS level Higher Lower Intracellular pH Acidic No acidic Metabolic rates Higher Lower.

Table 1. Targeting mitochondrial respiratory chain Arsenic trioxide ATO is used in the treatment of acute promyelocytic leukemia APL. Targeting VDACs VDACs, also known as mitochondrial porins, show high similarity between some animals especially mice and humans.

Targeting NOX Several studies have shown that some drugs and agents including, paclitaxel taxol , ionizing radiation, niclosamide, AGX, AG with effect on NOX induces ROS generation. Targeting p53 P53 act as a transcription factor to regulate the expression of many pro-oxidant genes.

References 1. Antioxidants are chemicals that interact with and neutralize free radicals , thus preventing them from causing damage. The body makes some of the antioxidants that it uses to neutralize free radicals.

These antioxidants are called endogenous antioxidants. However, the body relies on external exogenous sources, primarily the diet, to obtain the rest of the antioxidants it needs. These exogenous antioxidants are commonly called dietary antioxidants.

Fruits, vegetables, and grains are rich sources of dietary antioxidants. Some dietary antioxidants are also available as dietary supplements 1 , 3. Examples of dietary antioxidants include beta-carotene , lycopene , and vitamins A, C, and E alpha-tocopherol.

The mineral element selenium is often thought to be a dietary antioxidant, but the antioxidant effects of selenium are most likely due to the antioxidant activity of proteins that have this element as an essential component i.

In laboratory and animal studies , the presence of increased levels of exogenous antioxidants has been shown to prevent the types of free radical damage that have been associated with cancer development. Therefore, researchers have investigated whether taking dietary antioxidant supplements can help lower the risk of developing or dying from cancer in humans.

Many observational studies , including case—control studies and cohort studies , have been conducted to investigate whether the use of dietary antioxidant supplements is associated with reduced risks of cancer in humans. Overall, these studies have yielded mixed results 5.

Because observational studies cannot adequately control for biases that might influence study outcomes, the results of any individual observational study must be viewed with caution. Randomized controlled clinical trials , however, lack most of the biases that limit the reliability of observational studies.

To date, nine randomized controlled trials of dietary antioxidant supplements for cancer prevention have been conducted worldwide. Many of the trials were sponsored by the National Cancer Institute.

The results of these nine trials are summarized below. Initial: no effect on risk of developing either cancer; decreased risk of dying from gastric cancer only Later: no effect on risk of dying from gastric cancer.

Initial: lower total cancer and prostate cancer incidence and all-cause mortality among men only; increased incidence of skin cancer among women only.