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Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 438-446

Oxidative stress marker in oral cancer: A review

1 Department of Oral Pathology and Microbiology, Pacific Dental College and Hospital, Debari, Udaipur, Rajasthan, India
2 Department of ENT, G.S. Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India

Date of Web Publication25-Jul-2016

Correspondence Address:
Payal Katakwar
Department of Oral Pathology & Microbiology, Pacific Dental College and Hospital, Airport Road, Debari, Udaipur, Rajasthan - 313 024
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.151935

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 > Abstract 

Oxygen derived species such as hydrogen peroxide, superoxide anion radical, hydroxyl radical (OH-), and singlet oxygen are well known to be cytotoxic and have been implicated in the etiology of a wide array of human diseases, including cancer. Various carcinogens may also partly exert their effect by generating reactive oxygen species (ROS) during their metabolism. Oxidative damage to cellular DNA can lead to mutations and may, therefore, play an important role in the initiation and progression of multistage carcinogenesis. ROS influences central cellular processes such as proliferation, apoptosis, and senescence which are implicated in the development of cancer. Understanding the role of ROS as key mediators in signaling cascades may provide various opportunities for pharmacological intervention.

Keywords: Hydroxyl radical, high pressure liquid chromatography, high pressure liquid chromatography electrochemical detection, mitogen-activated protein kinase, nitric oxide, reactive oxygen species, reactive nitrogen species, superoxide dismutase

How to cite this article:
Katakwar P, Metgud R, Naik S, Mittal R. Oxidative stress marker in oral cancer: A review. J Can Res Ther 2016;12:438-46

How to cite this URL:
Katakwar P, Metgud R, Naik S, Mittal R. Oxidative stress marker in oral cancer: A review. J Can Res Ther [serial online] 2016 [cited 2022 May 16];12:438-46. Available from: https://www.cancerjournal.net/text.asp?2016/12/2/438/151935

 > Introduction Top

Globally, oral and pharyngeal cancer is the sixth leading cancer site.[1] Carcinomas account for about 96% of all oral cancers and sarcomas for about 4%. The most common type of oral cancer is squamous cell carcinoma, which develops from the stratified squamous epithelium that lines the mouth and pharynx. This form of cancer accounts for approximately nine of every 10 oral malignancies.[2] It was towards the end of 18th century that oxygen emerged as the paragon among the elements which sustained life, promoted physical health, and stimulated mental vigor. But too much of even the best is bad as was shown by Paul Bert in 1878 that oxygen in high concentrations could damage brain, lungs, and other organs.[3] Today's concept of oxygen toxicity is not restricted only to hyperbaric oxygen, but primarily focuses on the stress caused by oxygen metabolites (oxygen free radicals or reactive oxygen species (ROS)) generated as an integral part of our daily life.

Disruption of the delicate balance between oxidants/antioxidants in body plays a causative role in carcinogenesis. Enhanced ROS or reactive nitrogen species (RNS) or both along with concomitant decrease in antioxidants is seen in various cancers including head and neck cancer.[4],[5],[6],[7],[8],[9]

Concept of oxidative stress and ROS

Oxygen is a highly reactive atom that is capable of becoming part of potentially damaging molecules commonly called “free radicals.” A free radical can be defined as chemical species possessing unpaired electron. ROS is a term which encompasses all highly reactive, oxygen-containing molecules, including free radicals.[10] Various free radicals are given below and free radical with their neutralizing antioxidant are described in [Table 1].
Table 1: Various ROS and corresponding neutralizing antioxidants

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  • Hydroperoxyl (per hydroxyl) radical
  • Superoxide radical
  • Hydrogen peroxide
  • Singlet oxygen and triplet oxygen
  • Nitric oxide radical (NO-)
  • Peroxynitrite (OONO-)
  • Hypochlorite radical (HOCl-).[11]

All are capable of reacting with membrane lipids, nucleic acids, proteins, enzymes, and other small molecules; resulting in cellular damage.[12]

Mechanism of action of free radicals

ROS can cause tissue damage by a variety of different mechanism which include:

  • DNA damage
  • Lipid peroxidation (through activation of cyclooxygenase (COX) and lipoxygenase pathway)
  • Protein damage including gingival hyaluronic acid and proteoglycans
  • Oxidation of important enzymes, for example, antiprotease such as, 1 antitrypsin
  • Stimulate proinflammatory cytokine which are released by monocytes and macrophages by depleting intracellular thiol compounds and activating nuclear factor kappa beta.[12]

Oxidative stress

The relation between free radicals and disease can be explained by the concept of 'oxidative stress' elaborated by Sies.[13] Oxidative stress is defined as a state in which oxidation exceeds the antioxidant systems in the body secondary to a loss of the balance between them.[14] Products of such biological damage are referred as biomarkers of oxidative stress.[15] In addition to reactive oxygen generated by the host tissue, the oral cavity is also susceptible to reactive oxygen created by inhalation of oxidizing agents in tobacco smoke and air pollution. The realization that ROS (free radicals) and oxidative stress play important role in the etiology and progression of major human degenerative diseases has triggered enormous and worldwide interest in endogenous and exogenous antioxidants.[14]


ROS can be produced from endogenous and exogenous substances. Potential endogenous sources include mitochondria, cytochrome P450 metabolism, peroxisomes, and inflammatory cell activation.[16] Exogenous sources include environmental agents such as non-genotoxic carcinogens, various xenobiotics, ultrasound, and microwave radiation.[17],[18] They have dual nature, on one hand they are necessary for normal cellular functions, but when in excess they can cause cellular damage and can lead to cancer. [Figure 1] illustrates the potential outcomes of reactive oxidative species when not counterbalanced by antioxidant defenses of the cell.[19]
Figure 1: Endogenous and exogenous sources of reactive oxygen species and their role in the development of cancer

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Mechanism of action of ROS in cancer

Cancer development is characterized by summative action of multiple events occurring in single cell. It can be described by three stages: Initiation, promotion, and progression. ROS is involved in all these stages. The effect of oxidative stress at a certain stage of carcinogenesis is directly proportionate to the type and the reactivity of radicals involved. Initiation results when a normal cell sustains a DNA mutation that, when preceded by a round of DNA synthesis, results in fixation of the mutation, producing an initiated cell. Initiation of cancer by ROS is supported by presence of oxidative DNA modifications in cancer tissues.[20] The promotion stage is characterized by clonal expansion of initiated cells, by induction of cell proliferation and/or inhibition of apoptosis.[17] Oxidative stress is strongly involved in this stage. ROS can stimulate expansion of mutated cell clones by temporarily modulating the genes which are related to proliferation or cell death [21] and by regulating activity of certain transcription factors such as nuclear factor-jB (NFjB), Nrf2, HIF, and p53;[22] which control cell growth and oncogenesis.[23] It can lead to NFjB activation, with subsequent induction of Genes encoding for proteins that inhibit apoptosis.[24] It can also act at signal transduction level to exert prosurvival functions. Oxidativestress can activate ERK/MEK and PI3K/AKT pathways. This could result in inactivation of proapoptotic proteins and up regulation of antiapoptotic genes.[25] A low level of oxidative stress can stimulate cell division in promotion stage, and thus promotes tumor growth.[26] This implies that ROS production during this stage is the main mechanism of ROS-related tumor promotion. ROS also contributes to the last stage of carcinogenesis; progression. In this stage, generation of large amounts of ROS may contribute to mutate, inhibit antiproteisases, upregulate Matrix-metalloproteinases (MMPs),[27],[28] and injure local tissues. Increased levels of oxidatively modified DNA bases may contribute to genetic instability and metastatic potential of tumor cells in fully developed cancer.[29] ROS is reported to be crucial for triggering angiogenic response, which is important in cancer metastasis.[30] This suggests that ROS is involved in all these stages of carcinogenesis. ROS, which are formed through various events and pathways, react with and damage cellular components and contribute to neoplastic transformation.[31],[32]

Oxidative DNA damage and cancer

Damage to DNA by ROS has been widely accepted as a major cause of cancer. ROS can damage DNA and the division of cells with unpaired or misrepaired damage leading to mutations. The majority of mutations induced by ROS appear to involve modification of guanine, causing G → T transversions,[33] single strand breaks, and instability formed directly or by repair processes. In human tumors, G to T transversions is the most frequent mutations in the p53 suppressor gene.[34] Elevated levels of modified bases in cancerous tissue may be due to the production of large amount of H2O2, which has found to be characteristic of human tumor cells. A study supported initiation of cancer by the presence of oxidative DNA modifications in cancer tissue.[35]

Oxidative stress in precancer and cancer

Tobacco (smoking and smokeless) use and excessive consumption of alcohol are amongst risk factor for oral cancer.[36],[37],[38] Increased oxidative and nitrosative stress associated with disturbances in antioxidant defense system have been implicated in the pathogenesis of several diseases, most notably oral cancer.[39],[40] It was first demonstrated by Nair et al., that aqueous extracts of areca nut and catechu were capable of generating superoxide anion and hydrogen peroxide at pH > 9.5. The areca nut induced production of ROS was enhanced by Fe2+, Fe3+, and Cu 2+; but inhibited by Mn 2+. The presence of Ca (OH)2 in slaked lime leads to alkaline conditions in the oral cavity, favoring ROS generation. Calcium hydroxide content of lime in the presence of areca nut is a major factor responsible for the formation of ROS, which causes oxidative damage in the DNA of buccal mucosa cells of betel quid (BQ) chewers.[41]

Continuous local irritation by panmasala, gutkha, or areca nut due to its fine particulate nature induces injury-related chronic inflammation, oxidative stress, and cytokine production leading to cell proliferation, cell senescence, or apoptosis; miscoding DNA adduct; and inhibit DNA repair activity.[42]

It also accelerates tumor migration by stimulating MMP-8 expression through MEK pathway in at least some carcinomas of the upper aerodigestive tract.[43] Arecoline alone has been reported to inhibit cell attachment, cell spreading, and cell migration in a dose-dependent manner in cultured human gingival fibroblasts (HGFs).[44] Addition of extracellular nicotine acted synergistically on the arecoline-induced cytotoxicity, indicating that arecoline may render human oral mucosal fibroblast (OMF) more vulnerable to other reactive agents in cigarettes via Glutathione-S-transferase (GST) reduction. These observations explain that patients who practice the combined habit of BQ chewing and cigarette smoking are at greater risk of contracting OC.[45]

Cigarette smoke, which is rich in carcinogens such as nitrosamines and polycyclic aromatic hydrocarbons,[46],[47] causes accumulation of 8-hydroxydeoxyguanosine (8-OHdG).[48],[49] Lungs from cigarette smokers contain two- to threefold higher 8-OHdG that could lead to mutations, some of which might be induced by oxygen free radicals, resulting in inflammatory responses, fibrosis, and tumor development. Urine obtained from smokers also has a four- to 10-fold elevation in altered nucleotides that are known to be produced by ROS.[50] Urinary 8-OHdG is a biomarker of oxidative stress, cancer, atherosclerosis, and diabetes.[51]

Tobacco chewing and smoking causes oxidant/antioxidant imbalance which elevates oxidative stress. This is accompanied by increased lipid peroxidation, oxidative DNA damage, damage to macro- and micro-molecules of cells, and disturbances of antioxidant defense which can induce malignant process. The heat (generated during smoking) as well as pH (change during chewing) of body fluids due to tobacco consumption affects formation and stabilization of free radicals.[52]

Free radicals are produced in excessive amounts in alcoholics. Ethanol is oxidized by cytochrome P450 2E1 (CYP2E1) to acetaldehyde which is further oxidized to acetate. Chronic ethanol ingestion can induce single nucleotide polymorphism of CYP2E1. Resulting increased CYP2E1 activity leads to increased generation of ROS which leads to lipid peroxidation and its products such as 4-hydroxynonenal (4HNE), which binds to DNA to form mutagenic adducts.[53]

Various oxidative stress markers are

Hydroxyl Radical (OH-)

OH- is considered to be the most reactive radical in biological systems. In contrast to superoxide radicals that are considered relatively stable and have constant, relatively low reaction rates with biological components, OH- are short-lived species possessing high affinity toward other molecules. OH- is a powerful oxidizing agent that can react at a high rate with most organic and inorganic molecules in the cell, including DNA, proteins, lipids, amino acids, sugars, and metals. The three main chemical reactions of OH-s include hydrogen abstraction, addition, and electron transfer.

Superoxide Ion Radical (O2/H2O2)

This species possesses different properties depending on the environment and pH. Due to its pKa of 4.8, superoxide can exist in the form of either O2 or, at low pH, hydroperoxyl (H2O2). The latter can more easily penetrate biological membranes than the charged form. Hence, considered as an important species. In organic solvents the solubility of O2 is higher, and its ability to act as a reducing agent is increased. It also acts as a powerful nucleophile, capable of attacking positively charged centers, and as an oxidizing agent that can react with compounds capable of donating H (e.g. ascorbate and tocopherol). The most important reaction of superoxide radicals is dismutation.

Hydrogen Peroxide (H2O2)

The result of the dismutation of superoxide radicals is the production of H2O2. There are some enzymes that can produce H2O2 directly or indirectly. Although H2O2 molecules are considered reactive oxygen metabolites, they are not radical by definition; they can, however, cause damage to the cell at a relatively low concentration (10 mM). They are freely dissolved in aqueous solution and can easily penetrate biological membranes. Their deleterious chemical effects can be divided into the categories of direct activity, originating from their oxidizing properties, and indirect activity in which they serve as a source for more deleterious species, such as OH or HClO. Direct activities of H2O2 include degradation of heme proteins; release of iron; inactivation of enzymes; and oxidation of DNA, lipids, SH groups, and keto acids.[54]


8-OHdG, an oxidized form of guanine, is a major oxidative DNA-damage product that can produce mutation. This compound causes A: T to C: C or G: C to T: A trans version mutations because of its base pairing with adenine as well as cytosine. Immunohistochemical accumulation of high levels of 8-OHdG was reported to occur in various human tumors, like high grade glioma, compared to adjacent, normal tissue or low grade glioma. Oxidative stress may play a role in tumor progression. A study by Kumar et al., indicated an increase in 8-OHdG levels in salivary cell's DNA of squamous cell carcinoma of head and neck patients and demonstrated a significant redox imbalance in cancer patients, suggesting their paramount importance in the development of squamous cell carcinoma of head and neck.[55]

Nitrotyrosine (ONOO)

The toxicity of NO is enhanced by its reaction with a super oxide to form ONOO. It or secondary metabolites can cause tyrosine nitration in protein, creating nitrotyrosine, a footprint detectable in vivo. The presence of ONOO has been demonstrated in various human diseases like atherosclerosis, myocardial ischemia, inflammatory bowel disease, and amyotrophic lateral sclerosis, as well as in toxic and carcinogenic models.[56],[57],[58]


NFjB is a transcriptional factor implicated in inflammation and immune activation and activated by oxidants and cytokines.[59] This factor normally reside in an inactive form in the cytoplasm and has been shown to enhance inducible nitric oxide synthase (iNOS) gene expression in different types of cells, like macrophages.[60] The finding supported the supposition that a NFjB-dependent, epithelia-derived mediator may be responsible for the induction of iNOS expression and suggested a therapeutic approach targeting NFjB.


COX catalyzes the formation of prostaglandins and other eicosanoids from arachidonic acid. COX-2 is induced at the site of inflammation following stimulation with proinflammatory agents, such as interleukin-1 (IL-1), tumor necrosis factor-alpha, and lipopolysaccharides.[61] Investigators have suggested that the release from inflammatory cells of NO, which is synthesized from L-arginine by the action of iNOS, increases COX-2 activity.[62] COX-2 overexpression is involved in cellular proliferation and carcinogenesis in different organs, and COX-2-specific inhibitors prevent lung carcinogenesis.[63]


GST-pi, a member of the family of phase II detoxification enzymes, catalyzes intracellular detoxification reactions, including the inactivation of electrophilic carcinogens by catalyzing their conjugation with glutathione.[64]


NO is synthesized in a variety of tissues via the catalytic activity of NOS. The inducible form, iNOS, is found predominantly in mononuclear phagocytes where it may be induced by endotoxins and/orcytokines; it is capable of producing high levels of NO. Although the role of NO in tumor biology remains controversial, most data indicate that it promotes tumor progression. More intense iNOS immunoreactivity was observed in high grade prostatic intraepithelial neoplasia (PIN) than benign prostatic hyperplasia and low-grade PIN samples.[65]

Heme Oxygenase 1 (HO-1)

HO-1, a heat shock protein, is the inducible isoform of the rate-limiting enzyme of heme degradation. It is induced by various stimuli, including heat shock, hyperoxia, and oxidative stress and represents a powerful endogenous protective mechanism against free radicals in a variety of pathological conditions.[66]

 > Methods for Determination of Ros and Radicals Top

Detection of ROS/RNS in biologic systems is often problematic. They have short half-life (seconds) and there are efficient and redundant systems to scavenge them. At cellular level specific ROS can be individually assessed in tissue or quantification of the oxidative damage of biomolecules in saliva, blood, or urine is another way of measuring these biomarkers. The only technique for direct detection of radicals is electron spin resonance,[67] which allows the detection of relatively stable radicals. Another technique is the spin trapping method in which a highly reactive radical, such as OH reacts with a trap molecule to produce a stable radical product that can be evaluated.[68] Other trapping procedures allow a radical to react with a detector molecule to yield a stable product that can then be evaluated using a variety of techniques, such as hydroxylation of salicylic acid,[69] the deoxyribose assay,[70],[71] the cytochrome c reduction assay for detection of superoxide radicals,[72] and detection of NO radicals by colored end-product compounds.[73] High pressure liquid chromatography (HPLC) or gas chromatography–mass spectrometry (GC-MS) analysis of 8-OHdG after enzymatic hydrolysis of DNA and assessment of oxidative base damage by the single-cell gel electrophoresis or comet assay [74] are two of the many Techniques utilized to detect DNA adducts and base modification. In the last stage of the peroxidation process, peroxides are decomposed to aldehydes like malondialdehyde (MDA), which can be detected by thiobarbituric acid that gives a pink color easily measurable. The end products of other aldehydes, for example, hexanal, can also be measured. All of these are termed thiobarbituric reactive species (TBARS).[75] This method is one of the most widely used assays to assess peroxidation in the whole organism. Measurements of light emission by low-level chemiluminescence [76] and offluorescence emanating from age pigments produced from the interaction of aldehydes (e.g. MDA) with side-chain amino groups of proteins, amino acids, or nucleic acid bases to form Schiff bases also serve as indices of oxidative stress.[77]

Evaluation of protein oxidative damage can be accomplished using the carbonyl assay.[78] Carbonyls are produced from the attack of ROS on amino acid residues in proteins and a specific determination using gel electrophoresis techniques. Other methods for directly evaluating enzymatic activity are spectroscopic measurements or gel-activity procedures; other methods employ immunocytochemistry.

Depletion of one antioxidant molecule causes changes in the level of overall antioxidant molecules and may be evaluated using a variety of techniques including biochemical, immunohistological, spectroscopical, and electrochemical.[79] The total antioxidant activity assay offers many advantages and is considered a useful tool for detecting oxidative stress phenomena in bodily fluids and tissues. It may serve as an appropriate tool for the evaluation of antioxidant therapy. Easier techniques for their measurements and low cost of evaluation can make them versatile and useful prognostic tool for identification of oral cancer patients with high risk for recurrence and oral precancer patients with high risk for oral cancer. [Figure 2] demonstrates alternative approaches for the direct determination of ROS.
Figure 2: Alternative methodologies for determination of oxidative stress

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ROS and signaling cascades

The ROS-activated signal transduction pathways are regulated by two distinct protein families—the mitogen-activated protein kinase (MAPK) and the redox sensitive kinases. The MAPK signaling pathways modulate gene expression, mitosis, proliferation, motility, metabolism, and programmed cell death.[80] ERK pathway has most commonly been associated with the regulation of cell proliferation. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) regulates several genes involved in cell transformation, proliferation, and angiogenesis.[81] The modification of gene expression by ROS has direct effects on cell proliferation and apoptosis through the activation of transcription factors including MAPK, AP-1, and NF-κB pathways. Oxidant-mediated AP-1 activation results in enhanced expression of cyclin D1 and Cdks, which in turn promotes entry into mitosis and cell division. ROS function as second messengers involved in activation of NF-κB by tumor necrosis factor and cytokines cause DNA damage, mutation, and altered gene expression which are the required participants in the process of carcinogenesis.[82]

Role of antioxidant


Antioxidants are substances or agents that scavenge reactive oxygen metabolites, block their generation, or enhance endogenous antioxidants capabilities.[83] High consumption of antioxidants was associated with a decreased risk of head and neck squamous cell carcinoma among smokers, drinkers, and those with both smoking and drinking habits.[84] They are abundant in fruits and vegetables as well as in other foods such as nuts, grains, some meats, poultry, and fish. Different enzymatic and nonenzymatic antioxidants with their antioxidant actions and their significance in carcinogenesis are given in [Table 2].[12],[17],[85],[86]
Table 2: Different enzymatic and nonenzymatic antioxidants with their antioxidant actions and their significance in carcinogenesis

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Antioxidants and oral mucosal lesions

Studies suggest the role of antioxidants in treatment of oral mucosal lesions particularly include oral leukoplakia, oral lichen planus, oral submucous fibrosis, and oral cancer. In several epidemiologic studies, low intakes of vitamin E, carotenoids, or both have been associated with a higher cancer risk. Smoking, a major risk factor, results in lower β-carotene concentrations in plasma and oral mucosal cells.[87]

Antioxidants and carcinogenesis

A first line of defense against ROS is protection against their formation, that is, prevention. A strategy of preventive antioxidation also works by channeling an attacking species into a less harmful product, hence lowering the risk of further damage. The next stage is interception, the process of final deactivation. In interception would come the strategies which will prevent chain reaction of free radicals and formation of nonradical and nonreactive end products. Another measure is to change the direction of radical function from more sensitive target sites to cellular compartments in which oxidative damage would be less deleterious. Such intercepting chain-breaking antioxidants vitamin E (tocopherol), vitamin C (ascorbic acid), vitamin A (carotene), urate, and bilirubin.[12] Nonenzymatic antioxidants like alpha-tocopherol is probably the most efficient compound in lipid phase. It maintains a steady state of peroxylradical reduction in the cellularmembranes.[88] Studies have reported lowered antioxidants or antioxidant capacity in blood and tissues of oral precancer and cancer.[89] This could be due to (i) increased utilization of antioxidants to scavenge ROS/RNS, (ii) poor antioxidant defense system in cancerous environment, (iii) inadequate production of antioxidant enzymes, and (iv) increased destruction of antioxidants by reactive oxygen metabolites. Lowered capacity to defense ROS/RNS might be one of the possible mechanisms operating in the progression of oral cancer.[6]

Mechanism of antioxidant against oxidative stress

Enzymatic and nonenzymatic antioxidant systems, work synergistically, and in combination with each other to protect cells and organ systems against free radical damage and therefore cancer. Cancer inhibitory properties of antioxidants are based on:[90],[91]

  • Immune mechanisms
  • Molecular genetics pathway
  • Depression of tumor angiogenesis activity.
  • Stimulation of cell differentiation.

In the hamster buccal pouch cancer model it was observed that beta-carotene and alpha-tocopherol stimulate the migration of cytokine-laden macrophages and lymphocytes to the sites of developing squamous cell carcinoma.[92] Antioxidant micronutrients inhibit angiogenesis in tumors by inhibiting transforming growth factor (TGF)-alpha. Retinoids promote cellular differentiation with resultant apoptosis of neoplastic cells.[93]

Antioxidants have the potential to prevent, inhibit, and reverse the multiple steps involved in oral carcinogenesis. Curcumin (diferuloylmethane), a yellow coloring agent present in turmeric, has been linked with suppression of mutagenesis.[94] It has been demonstrated that it downregulates smokeless tobacco extract (STE; khaini) or nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced NF-jB and COX-2 in oral premalignant and cancer cells in vitro.[95]

Lycopene, a bright red carotene and carotenoid pigment, is a phytochemical antioxidant. It helps to attenuate free radical-initiated oxidative reactions, particularly lipid peroxidation and DNA damage. It has antiproliferative and prodifferentaition properties. Preliminary in vitro evidence also indicates that Lycopene reduces cellular proliferation induced by insulin-like growth factors, which are potent mitogens, in various cancer cell lines. Lycopene kill oral cancer cells when added to culture. They believed it to be due to its ability to restore gap junction communication, which is believed to be destroyed in oral malignancies, suggesting its possible role in oral cancer management as an adjuvant therapy.[96],[97] The curative effect of lycopene in OSMF may be owing to an inhibition of abnormal fibroblasts, upregulation of lymphocyte resistance to stress, and suppression of inflammatory response.[98]

TN Uma Maheswari highlighted the role of vitamin E in the treatment of leukoplakia.[99] Antioxidant combinations (vitamin A, E, and C) had proved to be most effective with maximum clinical resolution (90%) recorded and regression of dysplasia recorded as 97.5%.[100] Recent studies by Rai et al., have proved that antioxidants such as vitamin C and E may be utilized in oral lichen plan us patients to counteract free radical-mediated cell disturbances.[101] Mouli et al., recommended use of vitamin E as an antioxidant in oral lesions. Vitamin E can inhibit reactions of the tobacco-specific nitrosamine (carcinogens) which undergo specific activation and detoxification process. Antioxidants such as β carotene, provitamin A, vitamin C, vitamin E, zinc, selenium, and spirulina are believed to have a preventive role against oral cancer.[102]

 > Conclusion Top

The causes of lifestyle diseases can be divided into three major categories, which are genetic, habitual, and environmental. Many of the genes that are associated with biological oxidative stress have been identified, with the genes for NOS and HO being considered as candidates for such diseases. However, lifestyle diseases are often multifactorial, so it is difficult to identify the causative factors. Recent progress in the field of molecular biology has made it possible to store massive amounts of genetic information on DNA microchips and has provided various efficient computer programs for analysis, thus promising rapid progress in this field. Many daily habits are closely associated with oxidative stress, which is augmented by smoking, drinking, and an irregular diet. When the energy intake related to major nutrients is calculated, lipids provide over 25%, reflecting this change. Many environmental factors can generate active oxygen species and DNA damage caused by such oxygen radicals is extremely serious because it may be related to carcinogenesis. To prevent the development of lifestyle diseases, instructions on how to lead a healthy life should be given individually depending on the level of antioxidant activity assessed by pertinent biomarkers. Individual genetic information should also be taken into consideration when giving such instructions. Such health issues may become central to medical care in the 21st century.

 > References Top

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