Oxidative Stress in Lung Cancer

C H A P T E R

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Oxidative Stress in Lung Cancer Wei Sheng Joshua Loke*, Mann Ying Lim* Inflammation and Infection Research Centre, Faculty of Medicine, University of New South Wales and Department of Respiratory Medicine, Prince of Wales Hospital, Randwick, Sydney NSW 2031, Australia

Craig R. Lewis Department of Medical Oncology, Prince of Wales Hospital, Randwick, Sydney NSW 2031, Australia

Paul S. Thomas Inflammation and Infection Research Centre, Faculty of Medicine, University of New South Wales and Department of Respiratory Medicine, Prince of Wales Hospital, Randwick, Sydney NSW 2031, Australia

List of Abbreviations

INTRODUCTION

AP-1  activator protein-1 CDKN2A  cyclin-dependent kinase inhibitor 2A H2O2  hydrogen peroxide IARC  International Agency for Research on Cancer IL-6 interleukin-6 IL-8 interleukin-8 KRAS  kirsten rat sarcoma NF-κB  nuclear factor kappa B NO  nitric oxide NO2  nitrogen dioxide O2•− superoxide O3 ozone OH-  hydroxyl radicals ONOO- peroxynitrite PAH  polycyclic aromatic hydrocarbons Q•− semiquinone R•  carbon-centered radials RNS  reactive nitrogen species RO•  alkoxyl radicals ROO•  peroxyl radicals ROS  reactive oxygen species SO2  sulphur dioxide STK11  serine/threonine kinase 11 TB tuberculosis TNF-α  tumor necrosis factor α TP53  tumor protein 53 UVA ultraviolet-A

The lung is a highly specialized human organ. It is richly vascularized and facilitates gaseous exchange through coordinated interactions between the chest and diaphragmatic musculature, the central nervous and the cardiovascular systems. Upon maturity, the lung has a surface area of approximately 140 m2. With the exception of the skin, the lung is the organ with the highest exposure to the ambient air.1,2 The average adult inhales about 10,000 L of air daily, which can be contaminated with cigarette smoke, diesel soot, vehicle exhaust, organic and mineral dusts, gases such as sulphur dioxide (SO2), ozone (O3), nitrogen dioxide, viruses, and microbial pathogens. Inhalation of these substances can result in the production of reactive oxygen and nitrogen species that are able to, through oxidation and nitrosylation, initiate a cascade of signaling events that induce in the production of pro-inflammatory chemokines and cytokines that injure the lung. Persistent inhalation results in enhanced production of reactive oxygen and nitrogen species, which may lead to chronic inflammation that precipitates pulmonary carcinogenesis as discussed in the following.1,2 Apart from exogenous sources, oxygen and nitrogen species can be produced endogenously by reducing molecular oxygen to water in the mitochondrial electron

* These authors have made an equal contribution to this work.

Cancer http://dx.doi.org/10.1016/B978-0-12-405205-5.00003-9

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© 2014 Elsevier Inc. All rights reserved.

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transport during respiration, by cellular enzymes (e.g., xanthine oxidase and P450 oxidase) and via the cyclooxygenase pathway.3 Furthermore, nitrogen species can be produced in response to hypoxic conditions.4 In order to mitigate these insults, the epithelium of the lung is covered by a thin layer of lining fluid (respiratory tract lining fluid) vested with several antioxidants,5 which can be categorized into enzymatic antioxidants (i.e., superoxide dismutase, catalase, glutathione peroxidase, and glutathioneS-transferase) and nonenzymatic antioxidants (i.e., glutathione, cysteine, thioredoxin, vitamins C and E, beta-carotene, and uric acid).6 This review outlines the etiology of lung cancer and the role of reactive oxygen and nitrogen species in pulmonary carcinogenesis.

LUNG CANCER Lung cancer is the most common type of cancer in the world. In 2008, there were an estimated 1.2 million new cases (12.7% of new cancers) and 1.3 million cancer deaths (18.2% of cancer deaths). Lung cancer is uncommon in young adults, with the average age of occurrence being more than 60. The prognosis of lung cancer remains poor, especially in patients presenting with advanced disease. The expected survival at five years for all patients is only 5 to 10%. Although recent studies have suggested a role for low-dose CT screening in high risk individuals based on smoking history, this has yet to be implemented into standard clinical practice.7 Lung cancer can be broadly categorized into two main histopathological subtypes, including small cell and non-small cell lung cancer (NSCLC). Adenocarcinoma, squamous cell carcinoma, and large cell carcinoma form the main histological types of NSCLC and account for about 85% of all lung cancers.8

ETIOLOGY OF LUNG CANCER The majority of lung cancers are associated with smoking, but it may occur in up to 10% of individuals who have no smoking history. Epidemiological studies have identified other factors associated with the risk of having lung cancer, including infection and pollution (environmental, occupational, and domestic).9

Tobacco Smoke Tobacco smoking remains the major risk factor for lung cancer. In most populations, tobacco smoking

accounts for 90% and 70 to 80% of lung cancer cases in men and women, respectively, and because it is such a prominent risk factor, the geographical and temporal patterns of lung cancer largely reflect population-level changes in duration, type, and dose of tobacco used and in smoking behavior.8 The smoke from cigarettes and other tobacco products contains numerous carcinogens and agents that cause inflammation. The relative risk of lung cancer in smokers compared to never-smokers is 8 to 15 in men and 3 to 10 in women. Although smoking increases the risk of all histological subtypes of lung cancer, the risk is strongest for squamous cell carcinoma, and thereafter small cell carcinoma and adenocarcinoma. Nonetheless, in the last few decades, the percentage of NSCLC as squamous cell carcinoma, which had been the predominant histological type of lung cancer, has been decreasing while the incidence of adenocarcinomas has been increasing. This has been attributed to changes in the smoking behavior (e.g., using filtered cigarettes, reducing inhalation) and the composition of tobacco products.8

Exposure to Environmental Smoke There exists an association between lung cancer and second-hand smoke. Lung cancer risk increases with both the number of cigarettes smoked by the smoking partner and the duration of exposure to second-hand smoke. When confounding factors such as active smoking and diet have been taken into account, the increased risk of lung cancer is in the order of 20 to 25%. This is supported by biological data. For instance, tobacco metabolites have been found in 90% of urine samples from children whose parents smoke.10 Moreover, it has been observed that lung cancer rates are higher in cities than in rural settings. Although this might be confounded by occupational exposure and tobacco smoking, the combined evidence suggests that urban air pollution is a possible risk factor for lung cancer. Nonetheless, the excess risk remains more than 20% in most urban areas.8

Infections The Human Papillomavirus (types 16 and 18) are well-known carcinogens and are commonly present in lung tumor tissue.11 In addition, individuals who have been infected with Mycobacterium tuberculosis (TB) are shown to be at higher risk of lung cancer, which is independent of their smoking status. Patients with old TB lesions are predisposed to having epidermal growth factor receptor (EGFR) mutations in these neoplasms, particularly exon 19 deletions.12

1.  OXIDATIVE STRESS AND CANCER

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Silica and Oxidants

Occupational Exposure Respiratory cancers are the most frequently acquired occupational malignancy. Asbestos, crystalline silica, polycyclic aromatic hydrocarbons, and heavy metals (e.g., cadmium) are recognized by the International Agency for Research on Cancer (IARC) as pulmonary carcinogens.9 In addition, radon, associated with uranium mines, has been established as a risk factor for lung cancer. The risk of lung cancer in never-smokers who are exposed to 0, 100, and 400 Bq/m3 of radon is 0.4%, 0.5%, and 0.7%, respectively. These risks are approximately 25 times higher in smokers.13

Tobacco smoke in the gas phase contains more than 1015 radicals per puff. Contrary to stable radicals found in the tar phase, the organic radicals in the gas phase are transient (i.e., lifetimes of less than 1 second) reactive oxygen- and carbon-centered radicals. They are quickly quenched by the respiratory tract lining fluid. It is a paradox that, in spite of their short lifetimes, high concentrations of radicals can be maintained and even increased in the gas phase for more than 10 minutes. This is because gas phase radicals exist in a steady state where they are continuously made and destroyed.17 It has been postulated that this steady state involves the slow oxidation of nitric oxide (NO) to nitrogen dioxide (NO2; Equation 3.5).

Domestic Exposure Indoor air pollution elevates one’s risk of having lung cancer. The strongest evidence is for fumes from high-temperature cooking using unrefined vegetable oil (e.g., rapeseed oil) and from the burning of coal and other solid fuels.14

TOBACCO SMOKING AND OXIDANTS Tobacco smoke is a complex amalgamation of more than 4,700 chemical compounds, which are dispersed in the tar and gas phases. The radicals present in these phases differ.15 Tobacco smoke in the tar phase consists of extremely high concentrations of radicals (1017 per gram). These radicals are stable and are largely organic. Semiquinone (Q•−), for example, is held in the tar matrix. It reacts with oxygen to form superoxide (O2•−; Equation 3.1), which consequently dismutates to form hydrogen peroxide (H2O2; Equation 3.2).



Q • − + O2 → Q + O2• −

(3.1)



2 O2• − + 2H + → O2 + H2 O2

(3.2)

Furthermore, the tar contains metal ions (e.g., iron) that, through the Fenton reaction, generate highly oxidizing hydroxyl radicals (OH−) from hydrogen peroxide (Equation 3.3).



H2 O2 + Fe (II) → HO • + HO − + Fe (III)

(3.3)

Hydroxyl radicals can also be formed as a result of the decomposition of peroxynitrite (ONOO−), which is a product of a reaction between nitric oxide and superoxide (Equation 3.4).16,17



O2 • − + NO → ONOO − → HO • + NO2

(3.4)

1 NO + O2 → NO2 2



(3.5)

Nitrogen dioxide then reacts with isoprene present in tobacco smoke to form carbon-centered radicals (R•; Equation 3.6). Carbon radicals then react with oxygen, forming peroxyl radicals (ROO•; Equation 3.7). These react with nitric oxide to form alkoxyl radicals (RO•) and more nitrogen dioxide (Equation 3.8).16

NO2 +

(isoprene)

(R•)

(3.6)



R • + O2 → ROO •

(3.7)



ROO • + NO → RO • + NO2

(3.8)

The oxidant burden placed on the lung by the previously mentioned exogenously-derived oxidants is further intensified in smokers who have higher numbers of alveolar macrophages (by two- to four-fold) and leukocytes (by 10-fold). Moreover, compared to nonsmokers, alveolar macrophages and leukocytes from tobacco smokers spontaneously release increased amounts of superoxide and hydrogen peroxide, thereby exacerbating the oxidative burden in the lung (Figure 4).18 In addition, hydrogen peroxide has been detected in increased amounts in the exhaled breath condensate in those with lung cancer.19

SILICA AND OXIDANTS Silica can be inhaled during hard-rock mining, sand-blasting, or grinding. There are different forms of silica: vitreous, crystalline, synthetic/mineral, amorphous/natural, and biogenic. Silica exposure results in severe alveolar inflammation sustained by

1.  OXIDATIVE STRESS AND CANCER

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3.  OXIDATIVE STRESS IN LUNG CANCER

FIGURE 3.1  Silica and Oxidants in the Alveolus. The inhaled silica reaches the alveolus and is ingested by alveolar macrophages. Alveolar macrophage ingested silica is either cleared or persists in the macrophage, resulting in a process called “frustrated phagocytosis,” which releases ROS and RNS (cell-derived). The alveolar macrophages then undergo apoptosis and release the silica, perpetuating the aforementioned process. Inhaled silica can also cause the alveolar epithelium to release ROS and RNS (particular-derived). The ROS and RNS produced via these two sources increase the oxidative burden on the alveolar epithelium.

oxidants present in the alveolar space. Upon inhalation, silica reaches the alveolar space where it is phagocytosed by alveolar macrophages. Depending on the surface characteristics, the silica particles are either cleared from the lungs by the macrophages or activate macrophages at the molecular and cellular levels. This results in the release of ROS and RNS. Eventually the macrophages undergo apoptosis and release the silica particles. Subsequent ingestion–reingestion cycles result in the release of more cell-derived ROS and RNS. Additionally, silica particles can react directly with alveolar and bronchiolar epithelium to form particle-derived ROS and RNS (Figure 3.1). These damage the alveolar and ­bronchiolar epithelium and may react with cell-derived ROS and RNS to yield peroxynitrite (ONOO−) from superoxide (O2•−) and nitric oxide (NO).20

surface and silicon-based surface radicals serve as two active centers for oxidant production. The iron centers yield HO• radicals via the Fenton reaction (Equation 3.9) or the Haber-Weiss cycle (Equations 3.10–3.13) when a reductant and trace amounts of iron are present.



Fe2 + → H2 O2 → Fe3 + + OH − + HO •

(3.9)



Fe3 + → reductant → Fe2 + + reductant

(3.10)



Fe2 + → O2 → Fe3 + + O2 − •

(3.11)

O2− • + H2 O → HO2• + OH − or O2• + 2H + + e − → H2 O2

(3.12)

2HO2• → H2 O2 + O2 O2− • + H2 O2 → HO • + OH − + O2

(3.13)

Particle-Generated Oxidants Oxidants can be either bound to the silica surface (surface radical) or formed when silica is placed in aqueous suspensions. The former are formed when silica is fractured or ground. When this occurs, the silicon–oxygen bonds are cleaved.21 Molecular oxygen then reacts at the sites of cleavage and produces several “surface-bound ROS” – SiO3•, Si02•, Si+O2•−.22 Oxidants can also be generated when silica is suspended in aqueous solution. Iron ions that are located in the redox and coordinative positions on the silica

Moreover, hydroxyl radicals can also be formed when surface radicals (SiO•, SiO2•, SiO3•, Si+-O2•−) come into contact with water (Equation 3.14) or hydrogen peroxide (Equations 3.15 and 3.16).23



-SiO • + H2 O → -SiOH + HO •

(3.14)



-SiOO • + H2 O2 → -SiOH + HO • + O2

(3.15)



-Si + O2• + H2 O2 → -SiOH + HO • + O2

(3.16)

1.  OXIDATIVE STRESS AND CANCER

Inflammation and Oxidative Stress

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ASBESTOS AND OXIDANTS Asbestos fibers may be inhaled during the mining, extraction, processing, and use of this fiber. It is now most commonly a problem for those in the construction industry, but previously was used widely in ship-building, boiler-making, plumbing, roofing, as well as insulation for heat and electricity. It is still a common problem and continues to be used in countries such as Russia, India, and those in Southeast Asia. The inhalation of asbestos results in the accumulation of macrophages in the alveolar space.24 The mechanisms underlying ROS production following asbestos inhalation are similar to those of silica (see earlier). Alveolar macrophages engulf the asbestos fibers and undergo a process of “frustrated phagocytosis.”25 Post inhalation, the asbestos fiber acquires a redox-active iron on its surface, which encourages the development of extremely reactive hydroxyl radicals from hydrogen peroxide through Fenton-catalyzed Haber-Weiss reactions (Equation 3.17). The iron can also catalyze the production of alkoxyl radical from organic hydroperoxides (Equation 3.18).25



O2− + H2 O2 → HO − + HO • + O2 Fe2 + + ROOH → Fe3 + + RO • + HO −

FIGURE 3.2  Domestic Cooking and Oxidants. Combusting of cooking oils and cooking at high temperature results in the production of polycyclic aromatic hydrocarbons (PAH). These, on exposure to ultraviolet radiation (UVA), become photo-excited and can produce reactive oxygen species (ROS) by transferring their energy to molecular oxygen.

(3.17) (3.18)

Alkoxyl and hydroxyl radical production leads to ROS-induced perturbation of DNA structure and function, which leads to pulmonary carcinogenesis.26

DOMESTIC COOKING AND OXIDANTS When food is grilled, fried, or stir-fried at high temperatures with cooking oil, the combustion of cooking oils release polycyclic aromatic hydrocarbons (PAH) into the environment. Moreover high temperature cooking also causes sugar and fat degradation and amino acid and protein pyrolysis. This adds to the concentration of PAH in the air.27 Upon ultraviolet-A (UVA) photo-irradiation, PAHs oxidize to a myriad of hydroxylated products, namely oxygenated PAH, PAH quinones, nitro-PAH, and halo-PAH.28 UVA photo-irradiation of these PAHderived products can absorb light energy and form various photo-excited substrates.29 They transfer energy via electron transfer to molecular oxygen to produce singlet oxygen (1O2) and superoxide radicals. These ROS participate in lipid peroxidation and can cause DNA damage (Figure 3.2).30

ROLE OF OXIDANTS IN NORMAL PHYSIOLOGY Oxidants have several roles in normal physiology. One example is the regulation of normal cell growth through the activation of transcription factors such as nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1).31 Apart from cell growth, activation of transcriptional factors NF-κB and AP-1 also initiates inflammation involved in the host defense of the lung.15 Moreover, oxidants are also important in inducing angiogenesis, apoptosis of mutated/damaged cells, and senescence, which are crucial in the conversion of normal cells to neoplastic ones.19

INFLAMMATION AND OXIDATIVE STRESS Upon exposure of the lung epithelium to oxidants, a protective mechanism, inflammation, is triggered in the lungs in an attempt to eliminate the toxins.32 As will be discussed next, the inflammatory process can induce genetic mutations through oxidative stress, resulting in lung cancer. Oxidants initiate inflammation by activating transcription factor NF-κB and AP-1 in the airway epithelial

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cells and macrophages.6,33 Transcription factors NF-κB and AP-1 are responsible for the gene transcription of downstream inflammatory cytokines such as interleukin-8 (IL-8), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6), which attract more inflammatory cells such as alveolar macrophages, neutrophils, and eosinophils to generate an inflammatory cascade.6,34,35 The recruited leukocytes in turn eliminate pathogens by producing oxidants as mentioned, including superoxide, nitric oxide, hydrogen peroxide, hydroxyl radical, peroxynitrite, and hydrochlorous acid. The oxidants can inactivate pathogens via halogenation or protein or lipid peroxidation. Following the destruction and removal of these foreign pathogens, inflammation settles.36 As such, in the attempt to eliminate toxins, neutrophils and macrophages produce oxidants that further augment the inflammation response.

OXIDATIVE STRESS LEADS TO DNA MUTATIONS AND LUNG CANCER Oxidants are highly reactive oxidizing agents due to the unpaired electrons, which readily attack DNA, proteins, and lipids (such as those in the cell membrane).37 Oxidants readily react with DNA bases to form DNA adducts, which are complexes formed from the covalent binding of DNA to molecules including carcinogens.38 DNA adducts can cause miscoding during DNA replication when an incorrect base is paired, resulting in permanent mutation following replication.39 Other changes to DNA include base alteration, base insertion, deletion, chromosomal translocation, single- or double-strand breaks, microsatellite instability, and the activation of oncogenes, which are directly associated with lung cancer (Figure 3.3).6,36,40–44 DNA changes are also seen in

mitochondrial DNA, which can be detected in the breath condensate.45 When sufficient damage from oxidative stress has accumulated, irreversible changes to DNA may confer the cells a survival advantage. This constitutes the “initiation step” in the three-step progression of cancer, namely initiation, promotion, and progression.42 This is especially true when mutations occur in critical coding regions such as those of oncogene or tumor suppressor genes, which will result in a loss of normal growth regulation, followed by uncontrolled cell proliferation.39,46,47 Chronic pulmonary obstructive disease (COPD secondary to smoking) is a well-established disease of chronic inflammation that is also triggered by oxidative stress from tobacco smoking.46 Genetic mutation is similarly conferred in COPD patients and COPD itself is known to accrue a 4.5-fold increase in risk of lung cancer48 and is thus viewed as a stepping stone toward lung cancer progression. Genetic mutation in lung cancer can occur in oncogenes such as K-ras, jun, and myc, or tumor suppressor genes such as TP53, CDKN2A, and STK11 although they most commonly occur in oncogene K-ras and tumor suppressor gene TP53.39,49-51 The most frequently observed mutations on TP53 in lung cancer are guanine→ thymine transversions followed by guanine→ adenine transitions. They mostly occur at codons 157, 158, 245, 248, 249, and 273. Mutations on K-ras, on the other hand, are mainly guanine→ thymine transversions with smaller numbers of guanine→ adenine transitions, and most commonly occur in codon 12.39 Proofreading mechanisms of DNA replication may attempt to repair or remove the damaged DNA via direct repair, double-strand break repair, cross-link repair, nucleotide excision, or base excision.52 When

FIGURE 3.3  Stepwise Progression toward Lung Carcinogenesis. Tobacco smoke and other sources of oxidants cause DNA adduct formation and mutation. These lead to mutations and loss of cellular growth controls, resulting in unencumbered proliferative growth and, finally, lung cancer. This process can be mitigated or halted when DNA is repaired.

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Summary Points

damaged beyond repair, the cell usually undergoes apoptosis.46 However, if any of the steps of reparation fails, or if damage to DNA is too extensive beyond the control of reparation, permanent mutations may occur in the DNA, resulting in oncogenesis.

LIPID AND PROTEIN PEROXIDATION Apart from DNA, lipids and proteins can also be attacked by oxidants, further increasing risk of mutations and malignancy. Lipid peroxidation is the breakdown of polyunsaturated phospholipids into more reactive lipid peroxides; for instance hydroperoxides, lipoperoxides, and toxic aldehydes (e.g., malondialdehyde).6,43,53 Not only does lipid peroxidation damage cells by impairing membrane function,53 products of lipid peroxidation also behave in a similar manner as free radicals with the ability to cause oxidative stress and react with DNA.43 While lipid peroxidation produces by-products that react with DNA, protein peroxidation may interfere with enzymes involved in the DNA reparative system such as DNA polymerase, thereby promoting genetic mutations.36 Simply put, oxidants promote proliferative cell growth via DNA toxicity as well as lipid and protein damage. Oxidation of DNA, lipids, and proteins may also lead to increased reactive species production, contributing to the vicious cycle of oxidative stress.

OXIDANT/ANTIOXIDANT DISEQUILIBRIUM Under normal physiology, oxidants are counterbalanced by endogenous antioxidants. In response to elevated levels of oxidants and oxidant-producing inflammatory cells, the local capacity of antioxidants can increase. Superoxide dismutase, catalase, glutathione associated enzymes, and manganese superoxide dismutase are among the antioxidants that have been demonstrated to be raised in smokers, suggesting that a counterbalance to the continuing insult is attempted.54 The balance between oxidants and antioxidants is delicate. In the event where the endogenous system is unable to completely ward off the pathogens or when the insults are persistent, chronic inflammation occurs. During chronic inflammation, there is simultaneous tissue injury (from inflammation) and repair. The production of oxidants is persistently increased as a result, exhausting the buffering capacity of antioxidants. This oxidant/antioxidant disequilibrium, favoring the former, results in oxidative stress.

ANTIOXIDANTS AND LUNG CANCER CHEMOPREVENTION There has been significant interest in the role of antioxidants as potential chemoprevention of lung cancer. Several large randomized clinical trials have examined this question. In patients with previously treated early stage lung cancer, placebo controlled studies randomized patients to receive antioxidants or retinoids with primary study outcomes including prevention of second primary tumors, recurrence, and survival.55,56 Neither of these trials showed any benefit in favor of the antioxidant treatment arm. Several studies and a subsequent meta-analysis57–60 have failed to show any impact on lung cancer incidence with antioxidant agents in patient populations at risk of lung cancer (based on smoking history) and two of these studies58,60 identified possible increased risk with antioxidant therapy. Based on results of these large trials there is no substantive evidence to support the role of antioxidants as chemopreventative agents for lung cancer.

CONCLUSION In summary, exogenous and endogenous sources of oxidants can result in oxidative stress. The body reacts by orchestrating an acute inflammatory response to alleviate this insult. While acute inflammation results in restoration of normal physiological functions in the majority of situations by replacing injured tissue with scar tissue, the persistence of oxidants in the alveolar microvasculature leads to chronic inflammation, which exacerbates the production of ROS/NOS. Elevated levels of ROS/RNS result in preneoplastic DNA mutations and growth factor activation, which eventually lead to malignant transformations. Therefore, lung diseases and events associated with chronic inflammation are the major risk factors of lung cancer. Cigarette smoking is not only in itself a major source of exogenous oxidants, but the chronic inflammation it triggers also leads to elevated levels of ROS and RNS, both of which contribute to oxidative stress in lung tissues.

SUMMARY POINTS • T  here exist numerous endogenous and exogenous sources of oxidants to which the lung is exposed. • This surplus of oxidants depletes natural alveolar antioxidants, resulting in oxidative stress. • Oxidative stress leads to the release of proinflammatory cytokines and damage at the cellular level.

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3.  OXIDATIVE STRESS IN LUNG CANCER

FIGURE 3.4  Oxidative Stress and Lung Carcinogenesis. Endogenous and exogenous sources of oxidants result in an oxidant/antioxidant disequilibrium, which causes cell damage. Prolonged oxidative injury can lead to lung cancer.

• P  rolonged inflammation results in DNA damage and mutation and an inhibition of cellular repair mechanisms, which predispose the cell to neoplastic transformation. • Based on results from several large trials, there exists no evidence to support the role of antioxidants as chemopreventative agents for lung cancer. • The mechanism underpinning oxidative stress and lung cancer is summarized in Figure 3.4.   

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