The Two Sides of Dietary Antioxidants in Cancer Therapy

*Musbau Adewumi Akanji, Heritage Demilade Fatinukun, Damilare Emmanuel Rotimi, Boluwatife Lawrence Afolabi and Oluyomi Stephen Adeyemi*

## **Abstract**

Cancer is a major cause of mortality around the world, representing about 13% of deaths on the planet. Among the available cancer treatments, chemotherapy is most frequently utilized compared to other treatments such as surgery and radiotherapy. Many dietary antioxidants have proven to effectively prevent oxidative stress, which has been noted in many disease pathogeneses, including cancer. However, during chemotherapy or radiotherapy treatment of cancer patients, antioxidants are used as an adjuvant treatment. The use of a proof-based technique is advised in determining the supplements most suited to cancer patients. Though there are numerous opinions about the dangers and advantages of antioxidants, it is reasonable to conclude that side effects caused by antioxidants, for now, remain unclear for patients during cancer treatment, aside from smokers during radiotherapy. In this report, details of the effectiveness of antioxidants on cancer treatment aiding in the reduction of cancer therapy side effects are discussed.

**Keywords:** antioxidants, chemotherapy, dietary supplements, polyphenolics, radiotherapy

## **1. Introduction**

Cancer is a wide collection of diseases that can begin in practically any organ or tissue of the body when abnormal cells develop and move beyond their space to attack surrounding areas and also spread to different organs [1]. There are numerous types of cancer such as breast cancer, skin cancer, bone cancer, lung cancer, colon cancer, prostate cancer and if left untreated, it results in serious harm and could eventually lead to death [2]. Different causes of cancer include hereditary variables, way of life, diet, exposure to various kinds of synthetic compounds, and radiation. The American Cancer Society has estimated the number of new cancer cases for the year 2020 in the United States is 1,806,590 cases and 606,520 deaths. Previously, the cancer death rate increased up until the year 1991, at which point, the numbers dropped ceaselessly from 2017, bringing about a general decrease of about 29% which is equivalent to 2.9 million fewer cancer deaths than as projected. This was attributed to the long-term decrease in death rates for the 4 main cancer types (colorectal, prostate, breast, and lung cancer) [3]. Among the reasons that can be mentioned for the reduction in the mortality rate of cancer patients are the

various techniques being used for treatment such as chemotherapy, surgery, and radiotherapy. Various kinds of cancer can proceed in abnormal ways, develop at different rates, and react to treatment differently, hence, each cancer treatment is focused on the specific cancer type. Cancer therapy used in the treatment of cancer patient includes surgery, chemotherapy, radiotherapy and more recently antioxidant have been proposed to benefit cancer patients during cancer therapy [2].

Antioxidants are substances that can neutralize the production of free radicals and counteract the oxidation process. Antioxidants can be classified based on their source; endogenous source (enzymes) and exogenous diets (carotenoids, flavonoids, phenolics, minerals, and vitamins) [4]. Antioxidants are naturally found abundant in dietary sources, and their consumption possesses great health benefits [5]. The use of dietary antioxidants mitigates oxidative stress which contributes majorly to several diseases. Plant nutrients including organic products, vegetables, tea, grains, red wine, nuts, spices, and flavors give a huge sum and variety of antioxidants by preventing diseases. Dietary antioxidants are also a complex mixture of minerals (selenium, zinc, or copper) and micronutrients (vitamins A, C, and E) [6]. There are recommended antioxidants intake either as a diet with antioxidant activities or combined with antioxidant enzymes. Metals such as iron, zinc, manganese, copper, and selenium are considered cofactors of various enzyme antioxidants, and some nutrients (β-carotene, α-tocopherol, ascorbic acid, and folic acid) as sequestrate of reactive oxygen species (ROS) [7]. In light of this, this review discusses dietary antioxidants in cancer therapy in light of merits and demerits.

## **2. Oxidative stress**

A free radical is a particle capable of existing independently and has at least one unpaired electron in its outer shell. Most free radicals are profoundly reactive and unsteady as a result of the number of electrons. Therefore, they rapidly react with different substances to attain stability. Free radical attacks the nearest steady particle and acquire its electron, meanwhile, the attacked particle can turn into a free radical by loosing its electron and start a chain reaction course harming the living cells. Examples of free radicals are superoxide anion, lipid alkoxyl, lipid peroxide, lipid peroxyl, and hydroxyl radical. Reactive oxygen species (ROS) are radical subordinates, for example, hydrogen peroxide and singlet oxygen [8]. Free radicals are fundamentally reactive oxygen species (ROS) or reactive nitrogen species (RNS) comprising of singlet oxygen, hydrogen peroxide, superoxide radicals, intermediary nitrite, and nitric oxide (NO) [9]. The primary reactive oxygen species (ROS) are the superoxide (O2-), singlet oxygen (O2), hydrogen peroxide (H2O2), hydroxyl radicals (HO-), peroxyl and alkoxyl radicals (ROS- and RO-), and natural peroxides (ROOH). In the event of cellular damage caused by free radicals, for example, involving cellular amino acids, lipids, and DNA, reactive oxygen species (ROS) can activate enzymatic and non-enzymatic cell reactions, with the possibility of tampering with different metabolic processes and interfering with gene expression among other things.

Oxidative stress is an aftereffect of a variation in reactive oxygen species (ROS) and antioxidant resistances. Oxidative stress takes control of the development and function of the cell which can contribute to the pathogenesis of various conditions like neurodegenerative sickness, Parkinson's dementia, diabetes, cancer, immune system ailments, Alzheimer's ailment, cardiovascular diseases, carcinogenesis, asthma [10]. Oxidative stress predisposes cellular harm through oxidation of proteins, nucleic acids, and lipid, structural adjustment of the membranes, the

**167**

*The Two Sides of Dietary Antioxidants in Cancer Therapy*

harm induced may extend to the organs and become systemic [11]. Countering the effect of free radicals can be through a large intake of dietary antioxidants and specific antioxidant supplements as part of the diet. Though, some reports have suggested that combining several antioxidants is more viable in the long-term than single antioxidant substances. Therefore, antioxidants provide a great advantage in

Antioxidants act as scavengers of free radical or reactive oxygen species (ROS) and avert oxidation leading to several disease conditions. An antioxidant hinders the oxidation of lipids, DNA, sugar, and proteins at low concentrations. Antioxidants are found in plants, numerous foods, and some are synthesized in the body [13, 14]. In recent times, there has been increased utilization of natural products and reports have indicated that consumption of vegetables and fruits that contains antioxidants might be related to the decreased frequency of diseases activated by reactive oxygen species (ROS), such as cardiovascular diseases, cancer, etc. Oxidative stress and its damaging effects can be averted through the consumption of naturally occurring antioxidants [15]. Polyphenols and carotenoids (natural antioxidants) reveal natural activities as anti-atherosclerosis, anti-aging, anti-inflammatory, and anticancer [16]. Antioxidants function in the body to promote health and strength, particularly during old age. They ensure protection from damage to the tissues, and skin caused by the production of free radicals. In industries, they help to expand the food shelf-life

improving personal health by hindering several diseases conditions [12].

and are added in the skin-care products for anti-aging purposes [13].

The antioxidants are grouped into three fundamental classes:

flavonoids, carotenoids, vitamin C, vitamin E, etc.

reductase, protease, lipase, transferases, and so on [10].

The antioxidant system comprises of enzymatic and non-enzymatic antioxidants. Among the enzymatic antioxidants, are superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). The non-enzymatic antioxidant also contributes to the cellular redox balance, examples include hormones such as estradiol, melatonin, as well as certain nutrients, for example, vitamins E and C [17].

1.The principal line guard antioxidants which involve superoxide dismutase (SOD), glutathione reductase (GR), catalase (CAT), and minerals like Zn, Se,

2.The second line safeguard antioxidants which involve glutathione (GSH),

3.The third line safeguards antioxidants which involve a complex combination of chemicals responsible for fixing the damaged DNA, proteins, oxidized lipids, and peroxides. Examples are DNA repair enzymes, methionine sulphoxide

Dietary antioxidants are substances found in food and it ensures the protection of cells, tissues, and DNA against oxidative harm of free radicals. Dietary antioxidant supplements involve protein, starch, sodium, fiber, fat as well as minerals and vitamins. Dietary antioxidants having both antioxidant and pro-oxidant impacts involve nutrients (tocopherol, carotenoids, pro-vitamin A, ascorbic acid, basic micronutrients with physiological roles) and also involve phytochemicals and polyphenols. In a review, dietary consumption of anthocyanins (an antioxidant

*DOI: http://dx.doi.org/10.5772/intechopen.94988*

**2.1 Antioxidants**

and Cu, etc.

**2.2 Dietary antioxidants**

harm induced may extend to the organs and become systemic [11]. Countering the effect of free radicals can be through a large intake of dietary antioxidants and specific antioxidant supplements as part of the diet. Though, some reports have suggested that combining several antioxidants is more viable in the long-term than single antioxidant substances. Therefore, antioxidants provide a great advantage in improving personal health by hindering several diseases conditions [12].

## **2.1 Antioxidants**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

various techniques being used for treatment such as chemotherapy, surgery, and radiotherapy. Various kinds of cancer can proceed in abnormal ways, develop at different rates, and react to treatment differently, hence, each cancer treatment is focused on the specific cancer type. Cancer therapy used in the treatment of cancer patient includes surgery, chemotherapy, radiotherapy and more recently antioxidant have been proposed to benefit cancer patients during cancer therapy [2].

Antioxidants are substances that can neutralize the production of free radicals and counteract the oxidation process. Antioxidants can be classified based on their source; endogenous source (enzymes) and exogenous diets (carotenoids, flavonoids, phenolics, minerals, and vitamins) [4]. Antioxidants are naturally found abundant in dietary sources, and their consumption possesses great health benefits [5]. The use of dietary antioxidants mitigates oxidative stress which contributes majorly to several diseases. Plant nutrients including organic products, vegetables, tea, grains, red wine, nuts, spices, and flavors give a huge sum and variety of antioxidants by preventing diseases. Dietary antioxidants are also a complex mixture of minerals (selenium, zinc, or copper) and micronutrients (vitamins A, C, and E) [6]. There are recommended antioxidants intake either as a diet with antioxidant activities or combined with antioxidant enzymes. Metals such as iron, zinc, manganese, copper, and selenium are considered cofactors of various enzyme antioxidants, and some nutrients (β-carotene, α-tocopherol, ascorbic acid, and folic acid) as sequestrate of reactive oxygen species (ROS) [7]. In light of this, this review discusses dietary antioxidants in cancer therapy in light of merits and demerits.

A free radical is a particle capable of existing independently and has at least one unpaired electron in its outer shell. Most free radicals are profoundly reactive and unsteady as a result of the number of electrons. Therefore, they rapidly react with different substances to attain stability. Free radical attacks the nearest steady particle and acquire its electron, meanwhile, the attacked particle can turn into a free radical by loosing its electron and start a chain reaction course harming the living cells. Examples of free radicals are superoxide anion, lipid alkoxyl, lipid peroxide, lipid peroxyl, and hydroxyl radical. Reactive oxygen species (ROS) are radical subordinates, for example, hydrogen peroxide and singlet oxygen [8]. Free radicals are fundamentally reactive oxygen species (ROS) or reactive nitrogen species (RNS) comprising of singlet oxygen, hydrogen peroxide, superoxide radicals, intermediary nitrite, and nitric oxide (NO) [9]. The primary reactive oxygen species (ROS) are the superoxide (O2-), singlet oxygen (O2), hydrogen peroxide (H2O2), hydroxyl radicals (HO-), peroxyl and alkoxyl radicals (ROS- and RO-), and natural peroxides (ROOH). In the event of cellular damage caused by free radicals, for example, involving cellular amino acids, lipids, and DNA, reactive oxygen species (ROS) can activate enzymatic and non-enzymatic cell reactions, with the possibility of tampering with different metabolic processes and interfering with gene expression

Oxidative stress is an aftereffect of a variation in reactive oxygen species (ROS) and antioxidant resistances. Oxidative stress takes control of the development and function of the cell which can contribute to the pathogenesis of various conditions like neurodegenerative sickness, Parkinson's dementia, diabetes, cancer, immune system ailments, Alzheimer's ailment, cardiovascular diseases, carcinogenesis, asthma [10]. Oxidative stress predisposes cellular harm through oxidation of proteins, nucleic acids, and lipid, structural adjustment of the membranes, the

**166**

**2. Oxidative stress**

among other things.

Antioxidants act as scavengers of free radical or reactive oxygen species (ROS) and avert oxidation leading to several disease conditions. An antioxidant hinders the oxidation of lipids, DNA, sugar, and proteins at low concentrations. Antioxidants are found in plants, numerous foods, and some are synthesized in the body [13, 14]. In recent times, there has been increased utilization of natural products and reports have indicated that consumption of vegetables and fruits that contains antioxidants might be related to the decreased frequency of diseases activated by reactive oxygen species (ROS), such as cardiovascular diseases, cancer, etc. Oxidative stress and its damaging effects can be averted through the consumption of naturally occurring antioxidants [15]. Polyphenols and carotenoids (natural antioxidants) reveal natural activities as anti-atherosclerosis, anti-aging, anti-inflammatory, and anticancer [16]. Antioxidants function in the body to promote health and strength, particularly during old age. They ensure protection from damage to the tissues, and skin caused by the production of free radicals. In industries, they help to expand the food shelf-life and are added in the skin-care products for anti-aging purposes [13].

The antioxidant system comprises of enzymatic and non-enzymatic antioxidants. Among the enzymatic antioxidants, are superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). The non-enzymatic antioxidant also contributes to the cellular redox balance, examples include hormones such as estradiol, melatonin, as well as certain nutrients, for example, vitamins E and C [17].

The antioxidants are grouped into three fundamental classes:


## **2.2 Dietary antioxidants**

Dietary antioxidants are substances found in food and it ensures the protection of cells, tissues, and DNA against oxidative harm of free radicals. Dietary antioxidant supplements involve protein, starch, sodium, fiber, fat as well as minerals and vitamins. Dietary antioxidants having both antioxidant and pro-oxidant impacts involve nutrients (tocopherol, carotenoids, pro-vitamin A, ascorbic acid, basic micronutrients with physiological roles) and also involve phytochemicals and polyphenols. In a review, dietary consumption of anthocyanins (an antioxidant

found in berries) was revealed about 8% decrease in hypertensive condition [18]. Dietary nutrients have also shown significant improvement in bodily functions such as brain health, improved nervous system metabolism, and so on [19].

Since scientific evidence established the role of free radicals in the pathogenesis of diseases such as cardiovascular diseases, cancer among others, there have been considerable studies towards natural antioxidant properties to ameliorate such effects. The dietary antioxidant can have useful impacts on the body by scavenging free radicals and also the redox potential if they are available in tissues at adequate concentrations. For some dietary phytochemicals, direct antioxidants intake for some disease condition might be less significant to health than others as well as its consequences on cell signaling and gene expression [20]. There is a concern that the global consumption of fruits and vegetables is insufficient, leading to a decreased intake of antioxidants and predisposes to degenerative diseases [21].

#### **2.3 Examples of dietary antioxidants and their sources**

### *2.3.1 Vitamin C*

Vitamin C (ascorbic acid) is vital to the health of the body by acting as an intense scavenger of radical. Ascorbic acid is a water-soluble vitamin and a huge supplement for quick intestinal absorption. It is needed for the collagen synthesis in the body, essential in regulating norepinephrine from dopamine and function in tyrosine digestion. Insufficient intake of vegetables and fruits, the main sources of vitamin C, can prompt the inadequacy of this crucial nutrient in the body. Ascorbic acid is quickly exhausted and oxidized during oxidative stress. Examples of natural sources rich in vitamin C are grapefruits, pineapple, cherries, citrus fruits, potatoes, pepper, strawberries, gooseberry, broccoli, kiwi fruit, and paprika, etc. [22].

#### *2.3.2 Vitamin D*

Vitamin D is a fat-soluble vitamin known to assume an important role in bone and calcium homeostasis and function as an anti-inflammatory agent since it represses invulnerable the expression of cell cytokine and prompts monocyte/ macrophage to emit molecules which have a firm antibiotic impact. Its insufficiency can expand the danger of infectious diseases. Almost 95% of vitamin D is gathered in the epidermis of the skin on exposure to the sun, the rest is gotten from different dietary sources. In food, oily fish contains the largest amount of vitamin D, other sources include milk, orange, etc. [22].

#### *2.3.3 Vitamin E*

Vitamin E also called tocopherol is a fat-soluble vitamin. Vitamin E has an extremely wide capacity of preserving biological membrane and nucleic acids in the body from the attacks of free radicals. Vitamin E is rich in vegetables, vegetable oil, almonds, walnuts, etc. Vitamin E has been discovered to have repressive capacity on tumors [23].

#### *2.3.4 Flavonoids*

Plants have numerous flavonoids essential to mitigate the development of diseases. Basic flavonoids compounds involve anthocyanins, isoflavones, flavones, etc. Flavonoids destroy the free radicals by transforming them into phenolic radicals (inactive) after providing hydrogen to lipid compound radicals. Foods containing a

**169**

abnormalities [1].

*The Two Sides of Dietary Antioxidants in Cancer Therapy*

plant sources, for example, tomato, carrots, etc. [24].

large number of flavonoids involve herb, onions, blueberries, banana, and all citrus

These are dietary antioxidants that have exhibited action of photoprotection. In plants, these compounds are found in the photosynthetic parts where they are classified as extra light-collecting shades and shield from harm caused by sunlight. The photoprotective impacts of carotenoid-rich eating routine have been researched for its capacity to diminish the erythema (skin redness) size upon UV radiation exposure, though an extended period is necessary for a successful mediation. Among carotenoids, beta-carotene, lycopene, and lutein are gotten from various

There has been developing interest upheld by various epidemiological tests, on the possible gainful impacts of polyphenols on brain health. Polyphenol is micronutrients abundant in plant-determined nourishment which is also strong antioxidants. Fruits and beverages, for example, coffee, cocoa, and tea, and so on are significant dietary sources of polyphenols. Polyphenols are noted for their neuroprotective activities; protecting neurons against damage induced by neurotoxins, can suppress neuroinflammation, and the possibility to advance memory, learning, and psychological capacity. Recent evidence suggests that their beneficial impact includes a reduction in oxidative stress, an increase in defensive signaling, prompting the expression of genes that encode antioxidant enzymes, neurotrophic

Cancer is a major medical issue globally and is the second leading cause of death in the United States. A century ago, cancer was not all that normal, however, since the last few decades, its frequency has been rising alarmingly, presumably because of our evolving way of life and habits. Cancer is among the most dreaded illnesses of the 20th century and grows forward with the increasing rate in the 21st century. Cancer is the abnormal development of cells. Cancers are made of small cells that have lost the capacity to stop developing and can emerge from any body structure or organ. Caner is not easily detected in its early stages but might be recognized by

Cancer is a general term used in describing a group of diseases portrayed through independent development and the spread of a somatic clone. In this light, cancer must approach different cell pathways that empower it to disregard the typical requirements on cell development, change the local microenvironment to support its growth, attack through tissue boundaries, spread to different organs, and avoid immune system observation. No single cell program coordinates these behaviors, rather, there is a wide mass of pathogenic abnormalities from which singular cancers draw their combination, the shared traits of macroscopic features across tumors give a false representation of a huge heterogeneous scene of cell

Any time a cell divides, errors during the DNA replication process suggest that new mutations are present in the genomes of the daughter cells. Epigenetic marks (e.g. DNA methylation) are also replicated with limited precision. Larger-scope

chance via a laboratory test or radiological routine test [25].

*DOI: http://dx.doi.org/10.5772/intechopen.94988*

fruits, etc. [23].

*2.3.5 Carotenoids*

*2.3.6 Polyphenols*

**3. Cancer**

factors, and protective protein [7].

large number of flavonoids involve herb, onions, blueberries, banana, and all citrus fruits, etc. [23].

## *2.3.5 Carotenoids*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

found in berries) was revealed about 8% decrease in hypertensive condition [18]. Dietary nutrients have also shown significant improvement in bodily functions such

Since scientific evidence established the role of free radicals in the pathogenesis of diseases such as cardiovascular diseases, cancer among others, there have been considerable studies towards natural antioxidant properties to ameliorate such effects. The dietary antioxidant can have useful impacts on the body by scavenging free radicals and also the redox potential if they are available in tissues at adequate concentrations. For some dietary phytochemicals, direct antioxidants intake for some disease condition might be less significant to health than others as well as its consequences on cell signaling and gene expression [20]. There is a concern that the global consumption of fruits and vegetables is insufficient, leading to a decreased

as brain health, improved nervous system metabolism, and so on [19].

intake of antioxidants and predisposes to degenerative diseases [21].

Vitamin C (ascorbic acid) is vital to the health of the body by acting as an intense scavenger of radical. Ascorbic acid is a water-soluble vitamin and a huge supplement for quick intestinal absorption. It is needed for the collagen synthesis in the body, essential in regulating norepinephrine from dopamine and function in tyrosine digestion. Insufficient intake of vegetables and fruits, the main sources of vitamin C, can prompt the inadequacy of this crucial nutrient in the body. Ascorbic acid is quickly exhausted and oxidized during oxidative stress. Examples of natural sources rich in vitamin C are grapefruits, pineapple, cherries, citrus fruits, potatoes,

pepper, strawberries, gooseberry, broccoli, kiwi fruit, and paprika, etc. [22].

and calcium homeostasis and function as an anti-inflammatory agent since it represses invulnerable the expression of cell cytokine and prompts monocyte/ macrophage to emit molecules which have a firm antibiotic impact. Its insufficiency can expand the danger of infectious diseases. Almost 95% of vitamin D is gathered in the epidermis of the skin on exposure to the sun, the rest is gotten from different dietary sources. In food, oily fish contains the largest amount of vitamin D, other

Vitamin E also called tocopherol is a fat-soluble vitamin. Vitamin E has an extremely wide capacity of preserving biological membrane and nucleic acids in the body from the attacks of free radicals. Vitamin E is rich in vegetables, vegetable oil, almonds, walnuts, etc. Vitamin E has been discovered to have repressive capacity on

Plants have numerous flavonoids essential to mitigate the development of diseases. Basic flavonoids compounds involve anthocyanins, isoflavones, flavones, etc. Flavonoids destroy the free radicals by transforming them into phenolic radicals (inactive) after providing hydrogen to lipid compound radicals. Foods containing a

Vitamin D is a fat-soluble vitamin known to assume an important role in bone

**2.3 Examples of dietary antioxidants and their sources**

*2.3.1 Vitamin C*

*2.3.2 Vitamin D*

*2.3.3 Vitamin E*

tumors [23].

*2.3.4 Flavonoids*

sources include milk, orange, etc. [22].

**168**

These are dietary antioxidants that have exhibited action of photoprotection. In plants, these compounds are found in the photosynthetic parts where they are classified as extra light-collecting shades and shield from harm caused by sunlight. The photoprotective impacts of carotenoid-rich eating routine have been researched for its capacity to diminish the erythema (skin redness) size upon UV radiation exposure, though an extended period is necessary for a successful mediation. Among carotenoids, beta-carotene, lycopene, and lutein are gotten from various plant sources, for example, tomato, carrots, etc. [24].

#### *2.3.6 Polyphenols*

There has been developing interest upheld by various epidemiological tests, on the possible gainful impacts of polyphenols on brain health. Polyphenol is micronutrients abundant in plant-determined nourishment which is also strong antioxidants. Fruits and beverages, for example, coffee, cocoa, and tea, and so on are significant dietary sources of polyphenols. Polyphenols are noted for their neuroprotective activities; protecting neurons against damage induced by neurotoxins, can suppress neuroinflammation, and the possibility to advance memory, learning, and psychological capacity. Recent evidence suggests that their beneficial impact includes a reduction in oxidative stress, an increase in defensive signaling, prompting the expression of genes that encode antioxidant enzymes, neurotrophic factors, and protective protein [7].

## **3. Cancer**

Cancer is a major medical issue globally and is the second leading cause of death in the United States. A century ago, cancer was not all that normal, however, since the last few decades, its frequency has been rising alarmingly, presumably because of our evolving way of life and habits. Cancer is among the most dreaded illnesses of the 20th century and grows forward with the increasing rate in the 21st century. Cancer is the abnormal development of cells. Cancers are made of small cells that have lost the capacity to stop developing and can emerge from any body structure or organ. Caner is not easily detected in its early stages but might be recognized by chance via a laboratory test or radiological routine test [25].

Cancer is a general term used in describing a group of diseases portrayed through independent development and the spread of a somatic clone. In this light, cancer must approach different cell pathways that empower it to disregard the typical requirements on cell development, change the local microenvironment to support its growth, attack through tissue boundaries, spread to different organs, and avoid immune system observation. No single cell program coordinates these behaviors, rather, there is a wide mass of pathogenic abnormalities from which singular cancers draw their combination, the shared traits of macroscopic features across tumors give a false representation of a huge heterogeneous scene of cell abnormalities [1].

Any time a cell divides, errors during the DNA replication process suggest that new mutations are present in the genomes of the daughter cells. Epigenetic marks (e.g. DNA methylation) are also replicated with limited precision. Larger-scope

chromosol or part-chromosome losses or modifications [somatic copy number alternation (SCNAs)] and other structural modifications also occur at a standard frequency in many cancers. It is naturally occurring in the genetic modification that records the history of the cells in the tumor and since tumors are clonally derived; the entire cells in the tumor will carry the mutations in the main cancer cell, thus later-emerging subclones are recognizable by their sharing of a specific arrangement of variants, therefore, the order of clone advancement can be constructed by comparing the arrangement of mutation present in various cell tumor [26]. Cancer cells to meet their energy requirements, they depend on aerobic metabolism and also combined fatty acids, proteins, and nucleotides. Therefore, there is a constant need to expand the glucose supply needed to uphold diseases like diabetic-related hyperglycemia [27].

#### **3.1 Cancer types**

#### *3.1.1 Lung cancer*

Lung cancer is the most dangerous tumor, and the principal reason for cancer death worldwide in both genders combined. Globally, lung cancer occurrence and mortality on the general populace are essentially dictated by tobacco usage, the fundamental etiological factor in lung carcinogenesis [28]. The hazard factors for lung cancer involve ecological and hereditary hazard factors, all of which have an impact on tumor advancement and additionally influence patients' treatment [29]. Ladies have some unique hazard factors for lung cancer compared to men, and lung tumors in ladies have different pathologic conduct, results, and visualization in comparison to lung cancer growth in men [30]. The viability of lung cancer growth screening, utilizing computed tomography (CT) or chest X-ray (CXR), involving extra aides or not, such as sputum cytology, has been explored in various studies as asymptomatic at-risk populations [31].

#### *3.1.2 Breast cancer*

Breast cancer is the commonest cancer analyzed in the female population (excluding skin cancer) and reported the second highest cause of death among ladies after lung cancer [32]. There have been numerous analytic techniques for diagnosing early-stage breast cancer such as biopsy, breast MI, MRI, PET, ultrasonography, and mammography [33]. There are various hazardous factors, for example, sex, maturing, estrogen, family history, gene mutation, and an unhealthy lifestyle, which can contribute to the risk of breast cancer. Most breast cancers occur in ladies and the quantity of cases is multiple times more in ladies than that of men [34]. Various treatments can be utilized, for example, targeted therapy, hormonal therapy, radiation treatment, surgery, and chemotherapy [35].

#### *3.1.3 Prostate cancer*

Prostate cancer is another deadly cancer diagnosed in men and the fifth-highest cause of death around the world. Prostate cancer might show no symptoms in the beginning phase, regularly has slow movement, and may require little or even no treatment. Problems with urination have been the most common issue, however, records indicate that it may emerge from prostatic hypertrophy [36]. Screening for prostate cancer is initiated by measuring prostate-specific antigen (PSA) protein levels in the blood. A raised prostate-specific antigen (PSA) level indicates prostate

**171**

the patient [46].

*The Two Sides of Dietary Antioxidants in Cancer Therapy*

well as the health qualities of the patients [40].

show sensitivity or signals to help in early discovery [42].

cancer and other conditions, such as inflammation of the prostate and amplified prostate [37]. Prostate cancer has more victims of older men. Numerous patients with prostate cancer in the beginning stages obtain good results after various treatments involving prostatectomy, radiation therapy, hormonal therapy, etc. [38].

Colon cancer is the third most commonly diagnosed and second deadliest cancer for all genders joined. Natural affiliations and hereditary are the main risk factors. In patients, screening colonoscopy is required for tissue biopsy neurotic affirmation of colon carcinoma, such as baseline computed tomography (CT) of the chest, mid-region, and pelvis, and carcinoembryonic antigen (CEA) are favored cost-effective [39]. Chemotherapy and Surgery are the fundamental treatment choices for colon cancer, depending on the cancer stages and tumor area, as

Pancreatic cancer is one of the highest causes of cancer deaths in developed nations and one of the deadliest cancers worldwide. The two-fundamental tumors; pancreatic endocrine tumors (less than 5% of cases) and pancreatic cancer are adenocarcinoma (about 85% of cases) [41]. Finding the tumor at a treatable stage is extremely difficult, patients do not usually show symptoms and tumors do not

Other types of cancer including skin cancer, kidney cancer, lymphoma, bone

Cancer is caused by changes to the DNA within cells which are influenced by factors such as unhealthy diet, alcohol intake, tobacco use, infections, genetic tendency, ionizing radiation, toxins, obesity, inactive lifestyle, and other environ-

Cancer is among the primary causes of deaths globally, and in the previous years, numerous researches have concentrated on discovering new treatments other than the customary treatments which carry side effects. There are still numerous issues that must be addressed to improve cancer treatment, though much advancement has been accomplished in medication [44]. The number of cancer survivors continues to grow in the United States, notwithstanding the general declining age-normalized rates in men and stable rates in women. This shows an expanding number of new cancer analysis methods coming from the developing population as well as an increase in cancer survival due to advances in early detection and treatment. Many cancer survivors must adapt to the physical impacts of cancer and its treatment, possibly prompting functional and intellectual exhaustion [45]. There are numerous types of cancer treatment techniques based on the type of cancer and stage it has progressed to. There is no specific treatment or procedure rivaling cancer, in some cases, the treatment plan may utilize a mix of the treatment techniques to have a more effective treatment. Every one of the techniques has its side effect on

*DOI: http://dx.doi.org/10.5772/intechopen.94988*

*3.1.4 Colon cancer*

*3.1.5 Pancreatic cancer*

**3.2 Causes**

**3.3 Cancer therapy**

cancer, leukemia, liver cancer, etc.

mental factors [43] (**Figures 1** and **2**).

cancer and other conditions, such as inflammation of the prostate and amplified prostate [37]. Prostate cancer has more victims of older men. Numerous patients with prostate cancer in the beginning stages obtain good results after various treatments involving prostatectomy, radiation therapy, hormonal therapy, etc. [38].

## *3.1.4 Colon cancer*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

hyperglycemia [27].

**3.1 Cancer types**

*3.1.1 Lung cancer*

*3.1.2 Breast cancer*

*3.1.3 Prostate cancer*

asymptomatic at-risk populations [31].

chromosol or part-chromosome losses or modifications [somatic copy number alternation (SCNAs)] and other structural modifications also occur at a standard frequency in many cancers. It is naturally occurring in the genetic modification that records the history of the cells in the tumor and since tumors are clonally derived; the entire cells in the tumor will carry the mutations in the main cancer cell, thus later-emerging subclones are recognizable by their sharing of a specific arrangement of variants, therefore, the order of clone advancement can be constructed by comparing the arrangement of mutation present in various cell tumor [26]. Cancer cells to meet their energy requirements, they depend on aerobic metabolism and also combined fatty acids, proteins, and nucleotides. Therefore, there is a constant need to expand the glucose supply needed to uphold diseases like diabetic-related

Lung cancer is the most dangerous tumor, and the principal reason for cancer death worldwide in both genders combined. Globally, lung cancer occurrence and mortality on the general populace are essentially dictated by tobacco usage, the fundamental etiological factor in lung carcinogenesis [28]. The hazard factors for lung cancer involve ecological and hereditary hazard factors, all of which have an impact on tumor advancement and additionally influence patients' treatment [29]. Ladies have some unique hazard factors for lung cancer compared to men, and lung tumors in ladies have different pathologic conduct, results, and visualization in comparison to lung cancer growth in men [30]. The viability of lung cancer growth screening, utilizing computed tomography (CT) or chest X-ray (CXR), involving extra aides or not, such as sputum cytology, has been explored in various studies as

Breast cancer is the commonest cancer analyzed in the female population (excluding skin cancer) and reported the second highest cause of death among ladies after lung cancer [32]. There have been numerous analytic techniques for diagnosing early-stage breast cancer such as biopsy, breast MI, MRI, PET, ultrasonography, and mammography [33]. There are various hazardous factors, for example, sex, maturing, estrogen, family history, gene mutation, and an unhealthy lifestyle, which can contribute to the risk of breast cancer. Most breast cancers occur in ladies and the quantity of cases is multiple times more in ladies than that of men [34]. Various treatments can be utilized, for example, targeted therapy, hormonal

Prostate cancer is another deadly cancer diagnosed in men and the fifth-highest cause of death around the world. Prostate cancer might show no symptoms in the beginning phase, regularly has slow movement, and may require little or even no treatment. Problems with urination have been the most common issue, however, records indicate that it may emerge from prostatic hypertrophy [36]. Screening for prostate cancer is initiated by measuring prostate-specific antigen (PSA) protein levels in the blood. A raised prostate-specific antigen (PSA) level indicates prostate

therapy, radiation treatment, surgery, and chemotherapy [35].

**170**

Colon cancer is the third most commonly diagnosed and second deadliest cancer for all genders joined. Natural affiliations and hereditary are the main risk factors. In patients, screening colonoscopy is required for tissue biopsy neurotic affirmation of colon carcinoma, such as baseline computed tomography (CT) of the chest, mid-region, and pelvis, and carcinoembryonic antigen (CEA) are favored cost-effective [39]. Chemotherapy and Surgery are the fundamental treatment choices for colon cancer, depending on the cancer stages and tumor area, as well as the health qualities of the patients [40].

## *3.1.5 Pancreatic cancer*

Pancreatic cancer is one of the highest causes of cancer deaths in developed nations and one of the deadliest cancers worldwide. The two-fundamental tumors; pancreatic endocrine tumors (less than 5% of cases) and pancreatic cancer are adenocarcinoma (about 85% of cases) [41]. Finding the tumor at a treatable stage is extremely difficult, patients do not usually show symptoms and tumors do not show sensitivity or signals to help in early discovery [42].

Other types of cancer including skin cancer, kidney cancer, lymphoma, bone cancer, leukemia, liver cancer, etc.

## **3.2 Causes**

Cancer is caused by changes to the DNA within cells which are influenced by factors such as unhealthy diet, alcohol intake, tobacco use, infections, genetic tendency, ionizing radiation, toxins, obesity, inactive lifestyle, and other environmental factors [43] (**Figures 1** and **2**).

## **3.3 Cancer therapy**

Cancer is among the primary causes of deaths globally, and in the previous years, numerous researches have concentrated on discovering new treatments other than the customary treatments which carry side effects. There are still numerous issues that must be addressed to improve cancer treatment, though much advancement has been accomplished in medication [44]. The number of cancer survivors continues to grow in the United States, notwithstanding the general declining age-normalized rates in men and stable rates in women. This shows an expanding number of new cancer analysis methods coming from the developing population as well as an increase in cancer survival due to advances in early detection and treatment. Many cancer survivors must adapt to the physical impacts of cancer and its treatment, possibly prompting functional and intellectual exhaustion [45]. There are numerous types of cancer treatment techniques based on the type of cancer and stage it has progressed to. There is no specific treatment or procedure rivaling cancer, in some cases, the treatment plan may utilize a mix of the treatment techniques to have a more effective treatment. Every one of the techniques has its side effect on the patient [46].


#### **Figure 1.**

*Estimation of new cancer cases and deaths by sex, specifically the ten Main types of cancer in the United States, 2020. Estimates are regulated to the closest 10 and avoid basal cell, squamous cell skin tumors, and cancer which have not undergone metastasis except for urinary bladder [43].*

#### **Figure 2.**

*Estimated amount of US cancer survivors. Evaluations exclude cancer which has not undergone metastasis, except for urinary bladder and exclude basal cells or squamous cell skin cancer [45].*

#### *3.3.1 Available cancer treatments*

#### *3.3.1.1 Surgery*

Treatment of cancer by surgery is usually operated on non-hematological cancers. By surgical technique, the specialist expels the cancer tissues from the body. The surgical methodology can give a total or fractional fix for cancer. There might be side effects of the surgery based on the kind of cancer and the patients' health status. If cancer is metastasized to different areas of the body, at that point expelling cancer by the surgical process is impossible. The development of the cancer cells follows the Halstedian model of cancer progression where the tumors begin developing locally and spreading to the lymph nodes and the rest of the body. The treatment of cancer by surgery should be possible to cancers that are limited to an area and the tumor is small in size [47].

#### *3.3.1.2 Chemotherapy*

The technique of chemotherapy is done using drugs, generally known as anticancer medications, to destroy or pulverize the cancer cells. These medications

**173**

*The Two Sides of Dietary Antioxidants in Cancer Therapy*

interfere with the development of tumors and even damage the cancer cells. Chemotherapy is commonly considered a powerful technique for the treatment of cancer, though it can cause extreme side effects as it can also damage healthy cells or tissues. The side effects caused by chemotherapy depend on the type of cancer, its areas, and the patients' reaction to the specific kinds of chemotherapy treatment. The side effects on the cancer patient do not represent the viability of the treatment and disappear once the treatment process is finished. For the most part, chemotherapy medicines are recommended to a subject in an estimated amount over a time frame. In some cases, chemotherapy is administered at least two different medica-

tions at a time, this method is known as combination chemotherapy [48].

be adequately stimulated, and resolve effector capacities [49].

different approaches in both grown-ups and children [50].

age, sex, and the sort of medication utilized in the treatment [51].

Immunotherapy is a technique for cancer treatment that causes the immune system to fight cancer. This is otherwise called biologic therapy, which excites the immune system of the patient to fight cancer. Several studies have been conducted on immunotherapy for treating cancer, for example, monoclonal antibodies that block specific protein work by constraining to cancer cells, which train the immune system to perceive and fight the cancer cells. This technique for treatment does not have any significant side effects. Immunotherapy is divided into two principle immunotherapeutic; passive and active. The grouping depends on the component of the therapeutic agent utilized, as well as the status of the patients' immune system. The passive immunotherapeutic is utilized in cancer patients with feeble, unresponsive, or low responsive immune systems. To apply active immunotherapeutic, the patients' immune system should be able to react strongly when opposed,

Radiation therapy utilizes high portions of ionizing radiation to kill cancer cells

The hormone treatment fights cancer by evolving the number of hormones in the body to treat particular types of cancer that depend on the chemicals to develop and spread. This treatment technique is utilized for treating cancers of the breast, reproductive system, and prostate. The side effects depend on the type of cancer,

The targeted treatment of cancer focuses on the cells that re-empower the cancer

cells to develop, separation, and spread. The targeted treatment utilizes specific

and destroy the tumor tissues. This treatment is regularly utilized as a medical procedure to evacuate or lessen the size of the tumors. The radiation treatment is usually administered externally and internally to the target area and can be harmful to ordinary cells and prompt a reaction from ordinary cells because of these ionizing radiations. The radiation treatment utilizes unique equipment to carry estimated portions of radiation to the cancer cells. The radiation treatment destroys tumor cells by damaging their DNA either directly or by harming free radicals inside the cells which can hence damage the DNA. This treatment utilizes high energy ionizing radiation, for example, x-rays. This treatment has significant side effects that have

*DOI: http://dx.doi.org/10.5772/intechopen.94988*

*3.3.1.3 Immunotherapy*

*3.3.1.4 Radiation therapy*

*3.3.1.5 Hormone therapy*

*3.3.1.6 Targeted therapy*

*The Two Sides of Dietary Antioxidants in Cancer Therapy DOI: http://dx.doi.org/10.5772/intechopen.94988*

interfere with the development of tumors and even damage the cancer cells. Chemotherapy is commonly considered a powerful technique for the treatment of cancer, though it can cause extreme side effects as it can also damage healthy cells or tissues. The side effects caused by chemotherapy depend on the type of cancer, its areas, and the patients' reaction to the specific kinds of chemotherapy treatment. The side effects on the cancer patient do not represent the viability of the treatment and disappear once the treatment process is finished. For the most part, chemotherapy medicines are recommended to a subject in an estimated amount over a time frame. In some cases, chemotherapy is administered at least two different medications at a time, this method is known as combination chemotherapy [48].

#### *3.3.1.3 Immunotherapy*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

*have not undergone metastasis except for urinary bladder [43].*

**172**

*3.3.1 Available cancer treatments*

Treatment of cancer by surgery is usually operated on non-hematological cancers. By surgical technique, the specialist expels the cancer tissues from the body. The surgical methodology can give a total or fractional fix for cancer. There might be side effects of the surgery based on the kind of cancer and the patients' health status. If cancer is metastasized to different areas of the body, at that point expelling cancer by the surgical process is impossible. The development of the cancer cells follows the Halstedian model of cancer progression where the tumors begin developing locally and spreading to the lymph nodes and the rest of the body. The treatment of cancer by surgery should be possible to cancers that are limited to an area and the tumor is small in size [47].

*Estimated amount of US cancer survivors. Evaluations exclude cancer which has not undergone metastasis,* 

*except for urinary bladder and exclude basal cells or squamous cell skin cancer [45].*

*Estimation of new cancer cases and deaths by sex, specifically the ten Main types of cancer in the United States, 2020. Estimates are regulated to the closest 10 and avoid basal cell, squamous cell skin tumors, and cancer which* 

The technique of chemotherapy is done using drugs, generally known as anticancer medications, to destroy or pulverize the cancer cells. These medications

*3.3.1.1 Surgery*

**Figure 2.**

**Figure 1.**

*3.3.1.2 Chemotherapy*

Immunotherapy is a technique for cancer treatment that causes the immune system to fight cancer. This is otherwise called biologic therapy, which excites the immune system of the patient to fight cancer. Several studies have been conducted on immunotherapy for treating cancer, for example, monoclonal antibodies that block specific protein work by constraining to cancer cells, which train the immune system to perceive and fight the cancer cells. This technique for treatment does not have any significant side effects. Immunotherapy is divided into two principle immunotherapeutic; passive and active. The grouping depends on the component of the therapeutic agent utilized, as well as the status of the patients' immune system. The passive immunotherapeutic is utilized in cancer patients with feeble, unresponsive, or low responsive immune systems. To apply active immunotherapeutic, the patients' immune system should be able to react strongly when opposed, be adequately stimulated, and resolve effector capacities [49].

#### *3.3.1.4 Radiation therapy*

Radiation therapy utilizes high portions of ionizing radiation to kill cancer cells and destroy the tumor tissues. This treatment is regularly utilized as a medical procedure to evacuate or lessen the size of the tumors. The radiation treatment is usually administered externally and internally to the target area and can be harmful to ordinary cells and prompt a reaction from ordinary cells because of these ionizing radiations. The radiation treatment utilizes unique equipment to carry estimated portions of radiation to the cancer cells. The radiation treatment destroys tumor cells by damaging their DNA either directly or by harming free radicals inside the cells which can hence damage the DNA. This treatment utilizes high energy ionizing radiation, for example, x-rays. This treatment has significant side effects that have different approaches in both grown-ups and children [50].

#### *3.3.1.5 Hormone therapy*

The hormone treatment fights cancer by evolving the number of hormones in the body to treat particular types of cancer that depend on the chemicals to develop and spread. This treatment technique is utilized for treating cancers of the breast, reproductive system, and prostate. The side effects depend on the type of cancer, age, sex, and the sort of medication utilized in the treatment [51].

#### *3.3.1.6 Targeted therapy*

The targeted treatment of cancer focuses on the cells that re-empower the cancer cells to develop, separation, and spread. The targeted treatment utilizes specific

agents for the deregulated proteins of cancer cells. The small atoms of targeted therapy medication are inhibitors of enzymatic areas on the change, overexpressed, or critical proteins inside the cancer cells [52].

Other treatments include bone marrow transplant, cryoablation, and radiofrequency ablation.

### **4. Roles of dietary antioxidants in cancer therapy**

Numerous types of cancer have been associated with the relation between free radicals and DNA which can cause harmful impacts on the cell cycle and also prompt dire threats. Antioxidants in suitable portions indicate that they have a generally good effect in making the tumors progressively responsive towards chemotherapy and radiation therapy. They can repress the development of tumors specifically without interfering with typical cells. Antioxidants can ensure protection against the toxicity caused by chemotherapy by hindering cell expansion. Additionally, antioxidants have demonstrated to hold an advantageous ability to decrease harm by oxidative stress, lessening the issues joined with the production of ROS and neurodegenerative issues [53].

ROS are chemically reactive particles containing oxygen, created by cellular metabolism. A moderate amount of ROS assumes a fundamental role in managing cell multiplication and cell survival. Nonetheless, an increase in ROS levels can harm cell components, for example, lipids, proteins, and DNA causing an imbalance between cell reduction–oxidation (redox) conditions and cause disturbance of homeostasis. Constantly, increased reactive oxygen species (ROS) prompt extreme cell harm and lead to carcinogenesis by regulating cell signaling such as cell expansion, angiogenesis, and metastasis [54].

There are two kinds of antioxidant dosages utilized in cancer treatment; a preventive low portion, which restrains typical cells as well as tumor cells from developing, and a remedial high portion, which restrains the development of cancer cells without impacting typical cells. Ongoing tests demonstrated that certain conditions should be met before involving antioxidants in chemotherapy. Moreover, they do not hinder but improve the cytotoxic effect of chemotherapy while protecting the typical tissue which subsequently increases the patients' survival and therapeutic response [55].

Research has indicated that 35% of cancer can be prevented by dietary adjustments. Fruits and vegetables, which are wealthy in antioxidants, act defensively against some types of cancer. Plant nutrients that contain polyphenols have demonstrated to be viable antioxidant agents for the body, they appear to oppose cancer growth in prostate, lung, breast, tongue, gastric, larynx, and colon cancers [56]. Besides, supplements such as nutrients and minerals can lessen the risk of cancer by stimulating antioxidant activity, restraining the multiplication of cancerous cells, tending to DNA methylation, and advancing cell-cycle capture. In patients recently treated for cancer, a healthy eating routine rich in fruits and vegetables can alter biomarkers of cancer growth [57]. Notably, the redox status of the cancer cell which is under stress is not the same as the ordinary cell. Ordinary cells keep up cell homeostasis by the endogenous antioxidant mechanism which perfectly makes redox balance between the beginning and end of an overabundance of reactive oxygen species (ROS). Unfortunately, the remedial technique utilized in cancer treatment could cause an increased ROS level and also increases the endogenous ROS threshold level in cancer cells and may render ordinary cells of certain organs such as the kidney, liver, and heart ineffective against oxidative toxicity caused by oxidative stress. However, current research aims to distinguish the properties which may improve oxidative stress in cancer cells and protect ordinary cells from

**175**

*The Two Sides of Dietary Antioxidants in Cancer Therapy*

associated with the improvement of cancer [58].

oxidative harm. Extensive research conducted in recent years has indicated that plant-based nutrients have a high substance of phytochemicals such as flavonoids and polyphenols with chemopreventive properties that focus on some key factors

may develop such as weight reduction, or loss of appetite, and so on [59].

**4.1 The equivocal of dietary antioxidants in cancer therapy**

involve harmful impacts of expanding the cancer cell growth [60].

Some chemo-preventive compounds having antioxidant properties have been noted to have the potential to mitigate the cytotoxic effect of radiation treatment in cancerous cells while reducing its harm to ordinary cells and tissues. In such a manner, different research has demonstrated that phytochemicals soy isoflavones such as glycitein, show anti-carcinogenic properties to an extent using their antioxidant activities, and can be utilized as powerful radio-sensitizers to improve the viability of radiotherapy-mediated suppression of the development and metastatic capacity of tumors. As cancer patients experience treatment some unfavorable side effects

The ability of antioxidants to shield the cells from ROS created the premise of its production in food supplement enterprise, with the increase in the scientific literature on its helpful impacts and wide acknowledgment among the general public. Nonetheless, present research in cancer shows two different aspects of antioxidants. Antioxidants are both helpful as a treatment system for the cancer patient and also

DNA protection utilizing antioxidant therapy has been a productive choice for clinical trials. Flavonoids and phenolic acid are being noted as effective agents against the side effects of chemotherapy. A strong antioxidant such as coenzyme Q is mainly applied as a treatment in cancer, inflammation, and maturing. Application of coenzyme Q, for example on human epidermal cells, ensures protection against cell death initiated by reactive oxygen species (ROS) [61]. Supplements of vitamin C, one of the most abundant dietary antioxidants, have been found to ensure protection against oxidative harm caused by tobacco smoking reducing the risk factor of cancer. The relation between reactive oxygen species and cancer initiation is long-established. Other than the significant levels of ROS in environmental carcinogens such as tobacco smoking, reactive oxygen species (ROS) have been demonstrated to be basic for the transformation of cells caused by a gene that can transform a cell into a tumor cell or a loss of tumor suppressors. For instance, the downregulation of the p53 gene (a tumor suppressor) prompts increased reactive oxygen species (ROS) levels and antioxidantrelated medications hinder tumor formation in mice lacking this gene. Though every tumor is unique and the role of reactive oxygen species (ROS) and antioxidants can differ depending on hereditary, epigenetic, and environmental variation [62]. Discovery is being made implying that the impact which antioxidants have on cancer patients is truly harmful. It is important to note that a few antioxidants do behave as pro-oxidants under certain conditions. Another study showed that the b-carotene, a likely antioxidant, should be utilized cautiously, clear from its extremely reactive carotenoid radical development during the searching system of free radicals. The investigation indicated that the carotenoid radical structure which is scavenged through vitamin C can have harmful impacts on the initiation of cancer by UV-radiation with altering levels of vitamin C. The research implies that when antioxidants are taken by healthy persons, they present gainful impacts, however, when there is a beginning of tumor development, high portions of antioxidants should be avoided to stop the increase in expansion of tumor cells. It is also important to note that the antioxidants utilized as the cream can turn unstable through the responses related to UV-radiation which can prompt harmful impacts. These facts raise issues concerning antioxidant treatment, a potential solution could be the intake of selected

*DOI: http://dx.doi.org/10.5772/intechopen.94988*

*The Two Sides of Dietary Antioxidants in Cancer Therapy DOI: http://dx.doi.org/10.5772/intechopen.94988*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

or critical proteins inside the cancer cells [52].

ROS and neurodegenerative issues [53].

sion, angiogenesis, and metastasis [54].

**4. Roles of dietary antioxidants in cancer therapy**

radiofrequency ablation.

agents for the deregulated proteins of cancer cells. The small atoms of targeted therapy medication are inhibitors of enzymatic areas on the change, overexpressed,

Other treatments include bone marrow transplant, cryoablation, and

Numerous types of cancer have been associated with the relation between free radicals and DNA which can cause harmful impacts on the cell cycle and also prompt dire threats. Antioxidants in suitable portions indicate that they have a generally good effect in making the tumors progressively responsive towards chemotherapy and radiation therapy. They can repress the development of tumors specifically without interfering with typical cells. Antioxidants can ensure protection against the toxicity caused by chemotherapy by hindering cell expansion. Additionally, antioxidants have demonstrated to hold an advantageous ability to decrease harm by oxidative stress, lessening the issues joined with the production of

ROS are chemically reactive particles containing oxygen, created by cellular metabolism. A moderate amount of ROS assumes a fundamental role in managing cell multiplication and cell survival. Nonetheless, an increase in ROS levels can harm cell components, for example, lipids, proteins, and DNA causing an imbalance between cell reduction–oxidation (redox) conditions and cause disturbance of homeostasis. Constantly, increased reactive oxygen species (ROS) prompt extreme cell harm and lead to carcinogenesis by regulating cell signaling such as cell expan-

There are two kinds of antioxidant dosages utilized in cancer treatment; a preventive low portion, which restrains typical cells as well as tumor cells from developing, and a remedial high portion, which restrains the development of cancer cells without impacting typical cells. Ongoing tests demonstrated that certain conditions should be met before involving antioxidants in chemotherapy. Moreover, they do not hinder but improve the cytotoxic effect of chemotherapy while protecting the typical tissue which subsequently increases the patients' survival and therapeutic response [55]. Research has indicated that 35% of cancer can be prevented by dietary adjustments. Fruits and vegetables, which are wealthy in antioxidants, act defensively against some types of cancer. Plant nutrients that contain polyphenols have demonstrated to be viable antioxidant agents for the body, they appear to oppose cancer growth in prostate, lung, breast, tongue, gastric, larynx, and colon cancers [56]. Besides, supplements such as nutrients and minerals can lessen the risk of cancer by stimulating antioxidant activity, restraining the multiplication of cancerous cells, tending to DNA methylation, and advancing cell-cycle capture. In patients recently treated for cancer, a healthy eating routine rich in fruits and vegetables can alter biomarkers of cancer growth [57]. Notably, the redox status of the cancer cell which is under stress is not the same as the ordinary cell. Ordinary cells keep up cell homeostasis by the endogenous antioxidant mechanism which perfectly makes redox balance between the beginning and end of an overabundance of reactive oxygen species (ROS). Unfortunately, the remedial technique utilized in cancer treatment could cause an increased ROS level and also increases the endogenous ROS threshold level in cancer cells and may render ordinary cells of certain organs such as the kidney, liver, and heart ineffective against oxidative toxicity caused by oxidative stress. However, current research aims to distinguish the properties which may improve oxidative stress in cancer cells and protect ordinary cells from

**174**

oxidative harm. Extensive research conducted in recent years has indicated that plant-based nutrients have a high substance of phytochemicals such as flavonoids and polyphenols with chemopreventive properties that focus on some key factors associated with the improvement of cancer [58].

Some chemo-preventive compounds having antioxidant properties have been noted to have the potential to mitigate the cytotoxic effect of radiation treatment in cancerous cells while reducing its harm to ordinary cells and tissues. In such a manner, different research has demonstrated that phytochemicals soy isoflavones such as glycitein, show anti-carcinogenic properties to an extent using their antioxidant activities, and can be utilized as powerful radio-sensitizers to improve the viability of radiotherapy-mediated suppression of the development and metastatic capacity of tumors. As cancer patients experience treatment some unfavorable side effects may develop such as weight reduction, or loss of appetite, and so on [59].

#### **4.1 The equivocal of dietary antioxidants in cancer therapy**

The ability of antioxidants to shield the cells from ROS created the premise of its production in food supplement enterprise, with the increase in the scientific literature on its helpful impacts and wide acknowledgment among the general public. Nonetheless, present research in cancer shows two different aspects of antioxidants. Antioxidants are both helpful as a treatment system for the cancer patient and also involve harmful impacts of expanding the cancer cell growth [60].

DNA protection utilizing antioxidant therapy has been a productive choice for clinical trials. Flavonoids and phenolic acid are being noted as effective agents against the side effects of chemotherapy. A strong antioxidant such as coenzyme Q is mainly applied as a treatment in cancer, inflammation, and maturing. Application of coenzyme Q, for example on human epidermal cells, ensures protection against cell death initiated by reactive oxygen species (ROS) [61]. Supplements of vitamin C, one of the most abundant dietary antioxidants, have been found to ensure protection against oxidative harm caused by tobacco smoking reducing the risk factor of cancer. The relation between reactive oxygen species and cancer initiation is long-established. Other than the significant levels of ROS in environmental carcinogens such as tobacco smoking, reactive oxygen species (ROS) have been demonstrated to be basic for the transformation of cells caused by a gene that can transform a cell into a tumor cell or a loss of tumor suppressors. For instance, the downregulation of the p53 gene (a tumor suppressor) prompts increased reactive oxygen species (ROS) levels and antioxidantrelated medications hinder tumor formation in mice lacking this gene. Though every tumor is unique and the role of reactive oxygen species (ROS) and antioxidants can differ depending on hereditary, epigenetic, and environmental variation [62].

Discovery is being made implying that the impact which antioxidants have on cancer patients is truly harmful. It is important to note that a few antioxidants do behave as pro-oxidants under certain conditions. Another study showed that the b-carotene, a likely antioxidant, should be utilized cautiously, clear from its extremely reactive carotenoid radical development during the searching system of free radicals. The investigation indicated that the carotenoid radical structure which is scavenged through vitamin C can have harmful impacts on the initiation of cancer by UV-radiation with altering levels of vitamin C. The research implies that when antioxidants are taken by healthy persons, they present gainful impacts, however, when there is a beginning of tumor development, high portions of antioxidants should be avoided to stop the increase in expansion of tumor cells. It is also important to note that the antioxidants utilized as the cream can turn unstable through the responses related to UV-radiation which can prompt harmful impacts. These facts raise issues concerning antioxidant treatment, a potential solution could be the intake of selected

antioxidants according to the cancer cells movement and utilizing standard eating routine involving such antioxidants instead of the intake of direct supplements [14].

Adequate verification is required to determine the efficacy of different anticancer agents combined with antioxidant supplements. In a recent study, no reports have shown that they cause cancer growth or an increase in mortality rate. However, if antioxidant supplements are to be utilized as aids for cancer patients, more research is required for the combination of cancer therapy and dietary supplement. The use of unauthorized supplements should be avoided [60].

## **5. Conclusion**

There is uncertainty in determining whether antioxidants may have positively affected cancer treatment outcomes or prevent the harmful impacts of chemotherapy and radiotherapy. At first, it is important to consider all options of treatment and some patients are usually in good condition to endure the side effects of antioxidants. On second thought, some patients are not ready to endure the side effects of antioxidants, and to use treatment certain to work to some degree is more advisable. However, to be able to manage the side effects, these conditions should be revised; the dosage and types of antioxidants, the background and condition of the patient, and type of cancer and anticancer therapy. It is advisable to utilize a proof-based technique to choose the most appropriate supplement for cancer patients. Even though there are many opinions on the good and bad of antioxidants, it is difficult to clinically conclude that dietary antioxidants enhance therapeutic toxicities and also, there is no evidence of dietary antioxidant causing harm with cancer treatment, aside from smokers experiencing radiotherapy.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Musbau Adewumi Akanji1 , Heritage Demilade Fatinukun2 , Damilare Emmanuel Rotimi2 , Boluwatife Lawrence Afolabi2 and Oluyomi Stephen Adeyemi2 \*

1 Department of Biochemistry, University of Ilorin, Ilorin, Nigeria

2 Department of Biochemistry, Medicinal Biochemistry and Toxicology Laboratory, Landmark University, Omu-Aran, Nigeria

\*Address all correspondence to: yomibowa@yahoo.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**177**

*The Two Sides of Dietary Antioxidants in Cancer Therapy*

antioxidants and natural products in inflammation. Oxidative medicine and cellular longevity. 2016;4-16. DOI:

[9] Rahimi-Madiseh M, Malekpour-Tehrani A, Bahmani M, Rafieian-Kopaei M, The research and

development on the antioxidants in prevention of diabetic complications. Asian Pacific journal of tropical medicine. 2016;9:9:825-831. DOI; 10.1016/j.apjtm.2016.07.001.

[10] Sindhi V, Gupta V, Sharma K, Bhatnagar S, Kumari R, Dhaka N, Potential applications of antioxidants–A review. Journal of Pharmacy Research. 2013;7:9:828-835. DOI: 10.1016/j.

[11] Domazetovic V, Marcucci G,

[12] Alam M. N, Bristi N. J,

ajeassp.2016.1112.1126.

apjtm.2017.10.017.

[14] Sarangarajan R, Meera S,

Rafiquzzaman M, Review on in vivo and in vitro methods evaluation of antioxidant activity. Saudi

pharmaceutical journal. 2013;21:2:43- 152. DOI: 10.1016/j.jsps.2012.05.002.

[13] Aversa R, Petrescu R. V, Apicella A, Petrescu F. I, One can slow down the aging through antioxidants. American Journal of Engineering and Applied Sciences. 2016;9:4. DOI: 10.3844/

Rukkumani R, Sankar P, Anuradha G, Antioxidants: Friend or foe? Asian Pacific Journal of Tropical Medicine. 2017;10:12:1111-1116. DOI: 10.1016/j.

[15] Olas B, Berry phenolic antioxidants–

implications for human health?

Iantomasi T, Brandi M. L, Vincenzini M. T, Oxidative stress in bone remodeling: role of antioxidants. Clinical Cases in Mineral and Bone Metabolism. 2017;14:2:209. DOI: 10.11138/ ccmbm/2017.14.1.209.

jopr.2013.10.001.

10.1155/2016/5276130.

*DOI: http://dx.doi.org/10.5772/intechopen.94988*

[1] The, I. C. G. C, of Whole, T. P. C. A, Genomes Consortium, Pan-cancer analysis of whole genomes. Nature. 2020;578:(7793), 82. DOI: 10.1038/

[2] Subrahmanyam V, Ramachandran,

[3] Siegel R. L, Miller K. D, Jemal A, Cancer statistics, CA: a cancer journal for clinicians. 2020;70:1:7-30. DOI:

Liu T, Ma X, Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cellular Physiology and Biochemistry. 2017;44:2:32-553. DOI:

[5] Yeung A. W. K, Tzvetkov N. T, El-Tawil O. S, Bungǎu S. G,

Abdel-Daim M. M, Atanasov, A. G, Antioxidants: scientific literature landscape analysis. Oxidative medicine and cellular longevity, 2019;2-13. DOI:

[6] Goni I, Hernandez-Galiot A, Intake of Nutrient and Non-Nutrient Dietary Antioxidants. Contribution of Macromolecular Antioxidant Polyphenols in an Elderly

2019;11:9:2165. DOI: 10.3390/

research, 2016;11:6:865. DOI: 10.4103/1673-5374.184447.

[8] Arulselvan P, Fard M. T, Tan W. S, Gothai, S, Fakurazi S, Norhaizan M. E, Kumar S. S, Role of

[7] Lalkovicova M, Danielisova V, Neuroprotection and antioxidants.

nu11092165.

Neural regeneration

Mediterranean Population. Nutrients.

R. P, Significance of Dietary Antioxidants in Averting Cancer. J Carcinogen Mutagen. 2011;2:127. DOI:

10.4172/2157-2518.1000127.

[4] He L, He T, Farrar S, Ji L,

**References**

s41586-020-1969-6.

10.3322/caac.21590.

10.1159/000485089.

10.1155/2019/8278454.

*The Two Sides of Dietary Antioxidants in Cancer Therapy DOI: http://dx.doi.org/10.5772/intechopen.94988*

## **References**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

antioxidants according to the cancer cells movement and utilizing standard eating routine involving such antioxidants instead of the intake of direct supplements [14]. Adequate verification is required to determine the efficacy of different anticancer agents combined with antioxidant supplements. In a recent study, no reports have shown that they cause cancer growth or an increase in mortality rate. However, if antioxidant supplements are to be utilized as aids for cancer patients, more research is required for the combination of cancer therapy and dietary supplement.

There is uncertainty in determining whether antioxidants may have positively affected cancer treatment outcomes or prevent the harmful impacts of chemotherapy and radiotherapy. At first, it is important to consider all options of treatment and some patients are usually in good condition to endure the side effects of antioxidants. On second thought, some patients are not ready to endure the side effects of antioxidants, and to use treatment certain to work to some degree is more advisable. However, to be able to manage the side effects, these conditions should be revised; the dosage and types of antioxidants, the background and condition of the patient, and type of cancer and anticancer therapy. It is advisable to utilize a proof-based technique to choose the most appropriate supplement for cancer patients. Even though there are many opinions on the good and bad of antioxidants, it is difficult to clinically conclude that dietary antioxidants enhance therapeutic toxicities and also, there is no evidence of dietary antioxidant causing harm with cancer treatment, aside from smokers experiencing radiotherapy.

The use of unauthorized supplements should be avoided [60].

**176**

**Author details**

**Conflict of interest**

**5. Conclusion**

Musbau Adewumi Akanji1

Damilare Emmanuel Rotimi2

Landmark University, Omu-Aran, Nigeria

provided the original work is properly cited.

\*

The authors declare no conflict of interest.

\*Address all correspondence to: yomibowa@yahoo.com

1 Department of Biochemistry, University of Ilorin, Ilorin, Nigeria

Oluyomi Stephen Adeyemi2

, Heritage Demilade Fatinukun2

2 Department of Biochemistry, Medicinal Biochemistry and Toxicology Laboratory,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Boluwatife Lawrence Afolabi2

,

and

[1] The, I. C. G. C, of Whole, T. P. C. A, Genomes Consortium, Pan-cancer analysis of whole genomes. Nature. 2020;578:(7793), 82. DOI: 10.1038/ s41586-020-1969-6.

[2] Subrahmanyam V, Ramachandran, R. P, Significance of Dietary Antioxidants in Averting Cancer. J Carcinogen Mutagen. 2011;2:127. DOI: 10.4172/2157-2518.1000127.

[3] Siegel R. L, Miller K. D, Jemal A, Cancer statistics, CA: a cancer journal for clinicians. 2020;70:1:7-30. DOI: 10.3322/caac.21590.

[4] He L, He T, Farrar S, Ji L, Liu T, Ma X, Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cellular Physiology and Biochemistry. 2017;44:2:32-553. DOI: 10.1159/000485089.

[5] Yeung A. W. K, Tzvetkov N. T, El-Tawil O. S, Bungǎu S. G, Abdel-Daim M. M, Atanasov, A. G, Antioxidants: scientific literature landscape analysis. Oxidative medicine and cellular longevity, 2019;2-13. DOI: 10.1155/2019/8278454.

[6] Goni I, Hernandez-Galiot A, Intake of Nutrient and Non-Nutrient Dietary Antioxidants. Contribution of Macromolecular Antioxidant Polyphenols in an Elderly Mediterranean Population. Nutrients. 2019;11:9:2165. DOI: 10.3390/ nu11092165.

[7] Lalkovicova M, Danielisova V, Neuroprotection and antioxidants. Neural regeneration research, 2016;11:6:865. DOI: 10.4103/1673-5374.184447.

[8] Arulselvan P, Fard M. T, Tan W. S, Gothai, S, Fakurazi S, Norhaizan M. E, Kumar S. S, Role of antioxidants and natural products in inflammation. Oxidative medicine and cellular longevity. 2016;4-16. DOI: 10.1155/2016/5276130.

[9] Rahimi-Madiseh M, Malekpour-Tehrani A, Bahmani M, Rafieian-Kopaei M, The research and development on the antioxidants in prevention of diabetic complications. Asian Pacific journal of tropical medicine. 2016;9:9:825-831. DOI; 10.1016/j.apjtm.2016.07.001.

[10] Sindhi V, Gupta V, Sharma K, Bhatnagar S, Kumari R, Dhaka N, Potential applications of antioxidants–A review. Journal of Pharmacy Research. 2013;7:9:828-835. DOI: 10.1016/j. jopr.2013.10.001.

[11] Domazetovic V, Marcucci G, Iantomasi T, Brandi M. L, Vincenzini M. T, Oxidative stress in bone remodeling: role of antioxidants. Clinical Cases in Mineral and Bone Metabolism. 2017;14:2:209. DOI: 10.11138/ ccmbm/2017.14.1.209.

[12] Alam M. N, Bristi N. J, Rafiquzzaman M, Review on in vivo and in vitro methods evaluation of antioxidant activity. Saudi pharmaceutical journal. 2013;21:2:43- 152. DOI: 10.1016/j.jsps.2012.05.002.

[13] Aversa R, Petrescu R. V, Apicella A, Petrescu F. I, One can slow down the aging through antioxidants. American Journal of Engineering and Applied Sciences. 2016;9:4. DOI: 10.3844/ ajeassp.2016.1112.1126.

[14] Sarangarajan R, Meera S, Rukkumani R, Sankar P, Anuradha G, Antioxidants: Friend or foe? Asian Pacific Journal of Tropical Medicine. 2017;10:12:1111-1116. DOI: 10.1016/j. apjtm.2017.10.017.

[15] Olas B, Berry phenolic antioxidants– implications for human health?

Frontiers in pharmacology. 2018;9:78. DOI: 10.3389/fphar.2018.00078.

[16] Xu D. P, Li Y, Meng X, Zhou T, Zhou Y, Zheng J, Li H. B, Natural antioxidants in foods and medicinal plants: Extraction, assessment and resources. International journal of molecular sciences. 2017;18:1:96. DOI: 10.3390/ijms18010096.

[17] Addor F. A. S. A, Antioxidants in dermatology. Anais brasileiros de dermatologia. 2017;92:3:356-362. DOI: 1 0.1590/abd1806-4841.20175697.

[18] Peluso I, Dietary Antioxidants: Micronutrients and Antinutrients in Physiology and Pathology. 2019;4:6. DOI: 10.3390/antiox8120642.

[19] Huang Q, Liu H, Suzuki K, Ma S, Liu C, Linking what we eat to our mood: A review of diet, dietary antioxidants, and depression. Antioxidants. 2019;8:9:376. DOI: 10.3390/ antiox8090376.

[20] Gordon M. H, Significance of dietary antioxidants for health. International Journal of Molecular Sciences. 2012;13:1:173-179. DOI: 10.3390/ijms13010173.

[21] Varadharaj S, Kelly O. J, Khayat R. N, Kumar P. S, Ahmed N, Zweier J. L, Role of dietary antioxidants in the preservation of vascular function and the modulation of health and disease. Frontiers in cardiovascular medicine. 2017;4:64. DOI: 10.3389/ fcvm.2017.00064.

[22] Kaur G, Kathariya R, Bansal S, Singh A, Shahakar D, Dietary antioxidants and their indispensable role in periodontal health. Journal of food and drug analysis. 2016;24:2:239- 246. DOI: 10.1016/j.jfda.2015.11.003.

[23] Li S, Chen G, Zhang C, Wu M, Wu S, Liu Q, Research progress of natural antioxidants in foods for the treatment of diseases. Food Science and Human Wellness. 2014;3:3-4:110-116. DOI: 10.1016/j.fshw.2014.11.002.

[24] Petruk G, Del-Giudice R, Rigano, M. M, Monti D. M, Antioxidants from plants protect against skin photo aging. Oxidative medicine and cellular longevity. 2018;2;6. DOI: 10.1155/2018/1454936.

[25] Roy P. S, Saikia B. J, Cancer and cure: A critical analysis. Indian journal of cancer. 2016;53:3:441. DOI: 10.4103/0019-509X.200658.

[26] Graham T. A, Sottoriva A, Measuring cancer evolution from the genome. The Journal of pathology. 2017;241:2:183-191. DOI: 10.1002/path.4821.

[27] Avgerinos K. I, Spyrou N, Mantzoros C. S, Dalamaga M, Obesity and cancer risk: Emerging biological mechanisms and perspectives. Metabolism. 2019;92:121-135. DOI: 10.1016/j.metabol.2018.11.001.

[28] Malhotra J, Malvezzi M, Negri E, La-Vecchia C, Boffetta P, Risk factors for lung cancer worldwide. European Respiratory Journal. 2016;48:3:889-902. DOI: 10.1183/13993003.00359-2016.

[29] Tsao A. S, Scagliotti G. V, Bunn J. P. A, Carbone D. P, Warren G. W, Bai C, Adusumilli P. S, Scientific advances in lung cancer 2015. Journal of Thoracic Oncology. 2016;11:5:613-638. DOI: 10.1016/j.jtho.2016.03.012.

[30] De Groot P. M, Wu C. C, Carter B. W, Munden R. F, The epidemiology of lung cancer. Translational lung cancer research. 2018;7:3:220. DOI: 10.21037/ tlcr.2018.05.06.

[31] Blandin-Knight S, Crosbie P. A, Balata H, Chudziak J, Hussell T, Dive C, Progress and prospects of early detection in lung cancer. Open biology. 2017;7:9:170070. DOI: 10.1098/ rsob.170070.

**179**

*The Two Sides of Dietary Antioxidants in Cancer Therapy*

2016;22:30:6876. DOI: 10.3390/

[41] Ilic M, Ilic I, Epidemiology of pancreatic cancer. World journal of gastroenterology. 2016;22:44:9694. DOI:

10.3748/wjg.v22.i30.6876.

[42] Kleeff J, Korc M, Apte M,

La-Vecchia C, Johnson C. D, Biankin A. V, Neoptolemos J. P, Pancreatic cancer. Nature reviews Disease primers. 2016;2:1:1-22. DOI: 10.1038/

[43] Siegel R. L, Miller K. D, Jemal A, Cancer statistics, 2020. CA: a cancer journal for clinicians. 2020;70:1:7-30. DOI: 10.6004/jnccn.2020.0032.

Ciofani G, Innovative approaches for cancer treatment: current perspectives

Ecancermedicalscience. 2019;13:5-13. DOI: 10.3332/ecancer.2019.961.

Mariotto A. B, Rowland J. H, Yabroff K. R, Alfano C. M, Siegel R. L, Cancer treatment and survivorship statistics, 2019. CA: a cancer journal for clinicians.

[44] Pucci C, Martinelli C,

[45] Miller, K. D, Nogueira L,

2019;69:5:363-385. DOI: 10.3322/

[46] Roma-Rodrigues C, Mendes R, Baptista P. V, Fernandes A. R, Targeting tumor microenvironment for cancer therapy. International journal of

10.3390/ijms20040840.

DOI: 10.1002/wsbm.1412.

molecular sciences. 2019;20:4:840. DOI:

[47] Tringale K. R, Pang J, Nguyen Q. T, Image-guided surgery in cancer: A strategy to reduce incidence of positive surgical margins. Wiley Interdisciplinary Reviews: Systems Biology and Medicine. 2018;10:3:e1412.

[48] Wang J. J, Lei K. F, Han F, Tumor microenvironment: recent advances in various cancer treatments. Eur. Rev.

and new challenges.

caac.21551.

jcm8020201.

nrdp.2016.22.

*DOI: http://dx.doi.org/10.5772/intechopen.94988*

[32] DeSantis C, Siegel R, Bandi P, Jemal, A, Breast cancer statistics, 2011. CA: a cancer journal for clinicians. 2011;61:6:408-418. DOI: 10.3322/

[33] Wang L, Early diagnosis of breast cancer. Sensors. 2017;17:7:1572. DOI:

[34] Sun Y.S, Zhao Z, Yang Z.N, Xu F, Lu H.J, Zhu Z.Y, Shi W, Jiang J, Yao P.P, Zhu H.P, Risk factors and preventions of breast cancer. International journal of biological sciences. 2017;13:11:1387.

[35] Akram M, Iqbal M, Daniyal M, Khan A. U, Awareness and current knowledge of breast cancer. Biological research. 2017;50:1:33. DOI: 10.1186/

[36] Rawla P, Epidemiology of prostate cancer. World journal of oncology. 2019;10:2:63. DOI: 10.14740/wjon1166.

[38] Fujita K, Hayashi T, Matsushita M, Uemura M, Nonomura N, Obesity, inflammation, and prostate cancer. Journal of Clinical Medicine. 2019; 8:2:201. DOI: 10.1001/jama.2016.5989.

[39] Recio-Boiles A, Waheed A, Cagir B, Cancer, colon. In StatPearls [Internet]. StatPearls Publishing. Treasure Island (FL): StatPearls Publishing. 2020. https://www.ncbi.nlm.nih.gov/books/

[40] Hu T, Li Z, Gao C. Y, Cho C. H, Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World journal of gastroenterology.

[37] Grossman D. C, Curry S. J, Owens D. K, Bibbins-Domingo K, Caughey A. B, Davidson K. W, Krist A. H, Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Jama. 2018;319:18:1901-1913. DOI: 10.1001/

caac.20107.

10.3390/s17071572.

DOI: 10.7150/ijbs.21635.

s40659-017-0140-9.

jama.2018.3710.

NBK470380/.

*The Two Sides of Dietary Antioxidants in Cancer Therapy DOI: http://dx.doi.org/10.5772/intechopen.94988*

[32] DeSantis C, Siegel R, Bandi P, Jemal, A, Breast cancer statistics, 2011. CA: a cancer journal for clinicians. 2011;61:6:408-418. DOI: 10.3322/ caac.20107.

*Antioxidants - Benefits, Sources, Mechanisms of Action*

treatment of diseases. Food Science and Human Wellness. 2014;3:3-4:110-116. DOI: 10.1016/j.fshw.2014.11.002.

[24] Petruk G, Del-Giudice R, Rigano, M. M, Monti D. M, Antioxidants from plants protect against skin photo aging. Oxidative medicine and cellular longevity. 2018;2;6. DOI:

10.1155/2018/1454936.

[25] Roy P. S, Saikia B. J, Cancer and cure: A critical analysis. Indian journal of cancer. 2016;53:3:441. DOI:

[26] Graham T. A, Sottoriva A, Measuring cancer evolution from the genome. The Journal of pathology. 2017;241:2:183-191.

Mantzoros C. S, Dalamaga M, Obesity and cancer risk: Emerging biological mechanisms and perspectives. Metabolism. 2019;92:121-135. DOI: 10.1016/j.metabol.2018.11.001.

[28] Malhotra J, Malvezzi M, Negri E, La-Vecchia C, Boffetta P, Risk factors for lung cancer worldwide. European Respiratory Journal. 2016;48:3:889-902. DOI: 10.1183/13993003.00359-2016.

[29] Tsao A. S, Scagliotti G. V, Bunn J. P. A, Carbone D. P, Warren G. W, Bai C, Adusumilli P. S, Scientific advances in lung cancer 2015. Journal of Thoracic Oncology. 2016;11:5:613-638. DOI:

[30] De Groot P. M, Wu C. C, Carter B. W, Munden R. F, The epidemiology of lung cancer. Translational lung cancer research. 2018;7:3:220. DOI: 10.21037/

[31] Blandin-Knight S, Crosbie P. A, Balata H, Chudziak J, Hussell T, Dive C, Progress and prospects of early detection in lung cancer. Open biology.

2017;7:9:170070. DOI: 10.1098/

10.1016/j.jtho.2016.03.012.

tlcr.2018.05.06.

rsob.170070.

10.4103/0019-509X.200658.

DOI: 10.1002/path.4821.

[27] Avgerinos K. I, Spyrou N,

Frontiers in pharmacology. 2018;9:78. DOI: 10.3389/fphar.2018.00078.

[16] Xu D. P, Li Y, Meng X, Zhou T, Zhou Y, Zheng J, Li H. B, Natural antioxidants in foods and medicinal plants: Extraction, assessment and resources. International journal of molecular sciences. 2017;18:1:96. DOI:

10.3390/ijms18010096.

[17] Addor F. A. S. A, Antioxidants in dermatology. Anais brasileiros de dermatologia. 2017;92:3:356-362. DOI: 1

0.1590/abd1806-4841.20175697.

[18] Peluso I, Dietary Antioxidants: Micronutrients and Antinutrients in Physiology and Pathology. 2019;4:6. DOI: 10.3390/antiox8120642.

[19] Huang Q, Liu H, Suzuki K, Ma S, Liu C, Linking what we eat to our mood: A review of diet, dietary antioxidants,

and depression. Antioxidants. 2019;8:9:376. DOI: 10.3390/

[20] Gordon M. H, Significance of dietary antioxidants for health. International Journal of Molecular Sciences. 2012;13:1:173-179. DOI:

[21] Varadharaj S, Kelly O. J, Khayat R. N, Kumar P. S, Ahmed N, Zweier J. L, Role of dietary antioxidants in the preservation of vascular function and the modulation of health and disease. Frontiers in cardiovascular medicine. 2017;4:64. DOI: 10.3389/

[22] Kaur G, Kathariya R, Bansal S, Singh A, Shahakar D, Dietary antioxidants and their indispensable role in periodontal health. Journal of food and drug analysis. 2016;24:2:239- 246. DOI: 10.1016/j.jfda.2015.11.003.

[23] Li S, Chen G, Zhang C, Wu M, Wu S, Liu Q, Research progress of natural antioxidants in foods for the

antiox8090376.

10.3390/ijms13010173.

fcvm.2017.00064.

**178**

[33] Wang L, Early diagnosis of breast cancer. Sensors. 2017;17:7:1572. DOI: 10.3390/s17071572.

[34] Sun Y.S, Zhao Z, Yang Z.N, Xu F, Lu H.J, Zhu Z.Y, Shi W, Jiang J, Yao P.P, Zhu H.P, Risk factors and preventions of breast cancer. International journal of biological sciences. 2017;13:11:1387. DOI: 10.7150/ijbs.21635.

[35] Akram M, Iqbal M, Daniyal M, Khan A. U, Awareness and current knowledge of breast cancer. Biological research. 2017;50:1:33. DOI: 10.1186/ s40659-017-0140-9.

[36] Rawla P, Epidemiology of prostate cancer. World journal of oncology. 2019;10:2:63. DOI: 10.14740/wjon1166.

[37] Grossman D. C, Curry S. J, Owens D. K, Bibbins-Domingo K, Caughey A. B, Davidson K. W, Krist A. H, Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Jama. 2018;319:18:1901-1913. DOI: 10.1001/ jama.2018.3710.

[38] Fujita K, Hayashi T, Matsushita M, Uemura M, Nonomura N, Obesity, inflammation, and prostate cancer. Journal of Clinical Medicine. 2019; 8:2:201. DOI: 10.1001/jama.2016.5989.

[39] Recio-Boiles A, Waheed A, Cagir B, Cancer, colon. In StatPearls [Internet]. StatPearls Publishing. Treasure Island (FL): StatPearls Publishing. 2020. https://www.ncbi.nlm.nih.gov/books/ NBK470380/.

[40] Hu T, Li Z, Gao C. Y, Cho C. H, Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World journal of gastroenterology.

2016;22:30:6876. DOI: 10.3390/ jcm8020201.

[41] Ilic M, Ilic I, Epidemiology of pancreatic cancer. World journal of gastroenterology. 2016;22:44:9694. DOI: 10.3748/wjg.v22.i30.6876.

[42] Kleeff J, Korc M, Apte M, La-Vecchia C, Johnson C. D, Biankin A. V, Neoptolemos J. P, Pancreatic cancer. Nature reviews Disease primers. 2016;2:1:1-22. DOI: 10.1038/ nrdp.2016.22.

[43] Siegel R. L, Miller K. D, Jemal A, Cancer statistics, 2020. CA: a cancer journal for clinicians. 2020;70:1:7-30. DOI: 10.6004/jnccn.2020.0032.

[44] Pucci C, Martinelli C, Ciofani G, Innovative approaches for cancer treatment: current perspectives and new challenges. Ecancermedicalscience. 2019;13:5-13. DOI: 10.3332/ecancer.2019.961.

[45] Miller, K. D, Nogueira L, Mariotto A. B, Rowland J. H, Yabroff K. R, Alfano C. M, Siegel R. L, Cancer treatment and survivorship statistics, 2019. CA: a cancer journal for clinicians. 2019;69:5:363-385. DOI: 10.3322/ caac.21551.

[46] Roma-Rodrigues C, Mendes R, Baptista P. V, Fernandes A. R, Targeting tumor microenvironment for cancer therapy. International journal of molecular sciences. 2019;20:4:840. DOI: 10.3390/ijms20040840.

[47] Tringale K. R, Pang J, Nguyen Q. T, Image-guided surgery in cancer: A strategy to reduce incidence of positive surgical margins. Wiley Interdisciplinary Reviews: Systems Biology and Medicine. 2018;10:3:e1412. DOI: 10.1002/wsbm.1412.

[48] Wang J. J, Lei K. F, Han F, Tumor microenvironment: recent advances in various cancer treatments. Eur. Rev. Med. Pharmacol. Sci. 2018;22:3855- 3864. DOI: 10.3390/ijms20040840.

[49] Papaioannou N. E, Beniata O. V, Vitsos P, Tsitsilonis O, Samara P, Harnessing the immune system to improve cancer therapy. Annals of translational medicine. 2016;4:14:4-14. DOI: 10.21037/ atm.2016.04.01.

[50] Baskar R, Itahana K, Radiation therapy and cancer control in developing countries: Can we save more lives? International journal of medical sciences. 2017;14:1:13. DOI: 10.7150/ ijms.17288.

[51] Deli T, Orosz M, Jakab A, Hormone replacement therapy in cancer survivors–review of the literature. Pathology & Oncology Research. 2019;1-16. DOI: 10.1007/ s12253-018-00569-x.

[52] Ke X, Shen L, Molecular targeted therapy of cancer: The progress and future prospect. Frontiers in Laboratory Medicine. 2017;1:2:69-75. DOI: 10.1016/j. flm.2017.06.001.

[53] Gummadi P, Role of Antioxidants on Cancer and Neurodegenerative Disorders. Journal of Medical & Health Science. 2016;5:3:1-6. DOI: 10.2174/157015909787602823.

[54] Kim S. J, Kim H. S, Seo Y. R, Understanding of ROS-inducing strategy in anticancer therapy. Oxidative Medicine and Cellular Longevity. 2019. DOI: 10.1155/2019/5381692.

[55] Ammar H. O, Shamma R. N, Elbatanony R. S, Khater B, Antioxidants in Cancer Therapy: Recent Trends in Application of Nanotechnology for Enhanced Delivery. Scientia Pharmaceutica. 2020;88:1:5. DOI: 10.3390/scipharm88010005.

[56] Singh K, Bhori M, Kasu Y. A, Bhat G, Marar T, Antioxidants as precision weapons in war against cancer chemotherapy induced toxicity– Exploring the armoury of obscurity. Saudi Pharmaceutical Journal. 2018;26:2:177-190. DOI: 10.1016/j. jsps.2017.12.013.

[57] Liu Z, Ren Z, Zhang J, Chuang C. C, Kandaswamy E, Zhou, T, Zuo L, Role of ROS and nutritional antioxidants in human diseases. Frontiers in physiology. 2018;9:477. DOI: 10.3389/ fphys.2018.00477.

[58] Fatima S, Cancer Treatment with Pro and Antioxidant Agents. CPQ Cancer. 2018;1:4:01-06.

[59] Thyagarajan A, Sahu R. P, Potential contributions of antioxidants to cancer therapy: immunomodulation and radio sensitization. Integrative cancer therapies. 2018;17:2:210-216. DOI: 10.1177/1534735416681639.

[60] Yasueda A, Urushima H, Ito T, Efficacy and interaction of antioxidant supplements as adjuvant therapy in cancer treatment: a systematic review. Integrative cancer therapies. 2016;15:1:17-39. DOI: 10.1177/1534735415610427.

[61] Chowdhury W, Arbee S, Debnath S, Bin Zahur S, Akter S, Potent Role of Antioxidant Molecules in Prevention and Management of Skin Cancer. J Clin Exp Dermatol Res. 2017;8:3. DOI: 10.4172/2155-9554.1000393.

[62] Walton E. L, The dual role of ROS, antioxidants and autophagy in cancer. Biomedical Journal. 2016;39:2:89-92. DOI: 10.1016/j.bj.2016.05.001.

**181**

**Chapter 10**

**Abstract**

*Huda Mahmood Shakir*

fertility in a woman's life.

**1. Introduction**

NO2, nitrogen dioxide, MDA, malondiadehyde

the high rate of infertility and childlessness.

are the duration of infertility and female age [2].

mum duration before active intervention is considered.

Antioxidant and Infertility

Unexplained sub-fertility is commonly identified if couples fail to conceive after 1 yr. of everyday unprotected sexual intercourse even though investigations for ovulation, tubal patency and semen evaluation are ordinary. Many previous studies had shown that oxidative stress plays an important role in human fertility. Free radicals are neutralized by an elaborate antioxidant defense system. In a healthy body, prooxidants and antioxidants maintain a ratio and a shift in this ratio towards pro-oxidants gives rise to oxidative stress. There are two types of antioxidants in the human body: enzymatic and non-enzymatic antioxidants. Under normal conditions, antioxidants convert ROS to H2O to prevent overproduction of ROS. All cells in the human body are capable of synthesizing glutathione specially the liver. Free radicals appear to have a physiological role in female reproductive system in many different processes such as: oocyte maturation, fertilization, luteal regression, endometrial shedding and progesterone production by the corpus luteum. Protection from ROS is afforded by scavengers present in both male and female reproductive tract fluids, as well as in seminal plasma elevated concentrations of ROS in these environments may have detrimental effects on the spermatozoa, oocytes, sperm oocyte interaction and embryos both in the Fallopian tube and the peritoneal cavity; therefore oxidative stress modulates a host of reproductive pathologies affecting natural

**Keywords:** ROS, reactive oxygen species, OS, oxidative stress, NO, nitric oxide,

Reproductive failure is a significant public health concern. Infertility, carries significant personal, societal and financial consequences. One of the most important and underappreciated reproductive health problems in developing countries is

Causes of infertility can be found in about 90% of cases, about 10% of patients do not know why they can not conceive this is called unexplained infertility [1]. Unexplained infertility is a diagnosis of exclusion, when the standard investigation of both the female and male partner has ruled out other infertility diagnosis. A couple is considered to have unexplained infertility if the woman ovulated and had a normal and hysterosalpingogram, and the man a normal semen analysis. Critical factors to be considered in evaluating and managing unexplained infertility

In case of unexplained infertility, any form of treatment is speculated.

A period of three years of unexplained infertility is generally accepted as mini-

## **Chapter 10** Antioxidant and Infertility

*Huda Mahmood Shakir*

## **Abstract**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

precision weapons in war against cancer chemotherapy induced toxicity– Exploring the armoury of obscurity. Saudi Pharmaceutical Journal. 2018;26:2:177-190. DOI: 10.1016/j.

[57] Liu Z, Ren Z, Zhang J, Chuang C. C, Kandaswamy E, Zhou, T, Zuo L, Role of ROS and nutritional antioxidants in human diseases. Frontiers in physiology. 2018;9:477. DOI: 10.3389/

[58] Fatima S, Cancer Treatment with Pro and Antioxidant Agents. CPQ

[59] Thyagarajan A, Sahu R. P, Potential contributions of antioxidants to cancer therapy: immunomodulation and radio sensitization. Integrative cancer therapies. 2018;17:2:210-216. DOI: 10.1177/1534735416681639.

[60] Yasueda A, Urushima H, Ito T, Efficacy and interaction of antioxidant supplements as adjuvant therapy in cancer treatment: a systematic review. Integrative cancer therapies. 2016;15:1:17-39. DOI: 10.1177/1534735415610427.

[61] Chowdhury W, Arbee S, Debnath S, Bin Zahur S, Akter S, Potent Role of Antioxidant Molecules in Prevention and Management of Skin Cancer. J Clin Exp Dermatol Res. 2017;8:3. DOI:

[62] Walton E. L, The dual role of ROS, antioxidants and autophagy in cancer. Biomedical Journal. 2016;39:2:89-92. DOI: 10.1016/j.bj.2016.05.001.

10.4172/2155-9554.1000393.

jsps.2017.12.013.

fphys.2018.00477.

Cancer. 2018;1:4:01-06.

Med. Pharmacol. Sci. 2018;22:3855- 3864. DOI: 10.3390/ijms20040840.

Beniata O. V, Vitsos P, Tsitsilonis O, Samara P, Harnessing the immune system to improve cancer therapy. Annals of translational medicine. 2016;4:14:4-14. DOI: 10.21037/

[50] Baskar R, Itahana K, Radiation therapy and cancer control in

developing countries: Can we save more lives? International journal of medical sciences. 2017;14:1:13. DOI: 10.7150/

[51] Deli T, Orosz M, Jakab A, Hormone

[52] Ke X, Shen L, Molecular targeted therapy of cancer: The progress and future prospect. Frontiers in Laboratory Medicine. 2017;1:2:69-75. DOI: 10.1016/j.

[53] Gummadi P, Role of Antioxidants on Cancer and Neurodegenerative Disorders. Journal of Medical & Health Science. 2016;5:3:1-6. DOI: 10.2174/157015909787602823.

[54] Kim S. J, Kim H. S, Seo Y. R, Understanding of ROS-inducing

[55] Ammar H. O, Shamma R. N,

[56] Singh K, Bhori M, Kasu Y. A, Bhat G, Marar T, Antioxidants as

DOI: 10.1155/2019/5381692.

strategy in anticancer therapy. Oxidative Medicine and Cellular Longevity. 2019.

Elbatanony R. S, Khater B, Antioxidants in Cancer Therapy: Recent Trends in Application of Nanotechnology for Enhanced Delivery. Scientia Pharmaceutica. 2020;88:1:5. DOI: 10.3390/scipharm88010005.

replacement therapy in cancer survivors–review of the literature. Pathology & Oncology Research.

2019;1-16. DOI: 10.1007/ s12253-018-00569-x.

flm.2017.06.001.

[49] Papaioannou N. E,

atm.2016.04.01.

ijms.17288.

**180**

Unexplained sub-fertility is commonly identified if couples fail to conceive after 1 yr. of everyday unprotected sexual intercourse even though investigations for ovulation, tubal patency and semen evaluation are ordinary. Many previous studies had shown that oxidative stress plays an important role in human fertility. Free radicals are neutralized by an elaborate antioxidant defense system. In a healthy body, prooxidants and antioxidants maintain a ratio and a shift in this ratio towards pro-oxidants gives rise to oxidative stress. There are two types of antioxidants in the human body: enzymatic and non-enzymatic antioxidants. Under normal conditions, antioxidants convert ROS to H2O to prevent overproduction of ROS. All cells in the human body are capable of synthesizing glutathione specially the liver. Free radicals appear to have a physiological role in female reproductive system in many different processes such as: oocyte maturation, fertilization, luteal regression, endometrial shedding and progesterone production by the corpus luteum. Protection from ROS is afforded by scavengers present in both male and female reproductive tract fluids, as well as in seminal plasma elevated concentrations of ROS in these environments may have detrimental effects on the spermatozoa, oocytes, sperm oocyte interaction and embryos both in the Fallopian tube and the peritoneal cavity; therefore oxidative stress modulates a host of reproductive pathologies affecting natural fertility in a woman's life.

**Keywords:** ROS, reactive oxygen species, OS, oxidative stress, NO, nitric oxide, NO2, nitrogen dioxide, MDA, malondiadehyde

## **1. Introduction**

Reproductive failure is a significant public health concern. Infertility, carries significant personal, societal and financial consequences. One of the most important and underappreciated reproductive health problems in developing countries is the high rate of infertility and childlessness.

Causes of infertility can be found in about 90% of cases, about 10% of patients do not know why they can not conceive this is called unexplained infertility [1].

Unexplained infertility is a diagnosis of exclusion, when the standard investigation of both the female and male partner has ruled out other infertility diagnosis.

A couple is considered to have unexplained infertility if the woman ovulated and had a normal and hysterosalpingogram, and the man a normal semen analysis. Critical factors to be considered in evaluating and managing unexplained infertility are the duration of infertility and female age [2].

In case of unexplained infertility, any form of treatment is speculated.

A period of three years of unexplained infertility is generally accepted as minimum duration before active intervention is considered.

**Figure 1.** *Role of oxidative stress in fertility.*

Empirical treatment with clomiphene,intrauterine insemination are used in treatment of unexplained infertility, if failed, invitro fertilization is considered.

Because female ovary is the source of oocytes and regulating hormones, free radicals in the gynecologic environment is likely to be an important mediator of conception. Recently there is a growing evidence of possible role of highly reactive products of oxygen, termed free radicals, in infertility [3].

A free radical is any atom (e.g. oxygen, nitrogen) with at least one unpaired electron in the outermost [4]. Free radicals are neutralized by an elaborate antioxidant defense system. In a healthy body, pro-oxidants and antioxidants maintain a ratio and a shift in this ratio towards pro-oxidants gives rise to oxidative stress [3].

In this case free radical species which are unstable and highly reactive, will become stable by acquiring electrons from nucleic acids, lipids, proteins, carbohydrates or any nearby molecule causing a cascade of chain reactions resulting in cellular damage and diseas [5]. Because free radicals are unstable, and difficult to measure, traditional indices of oxidative stress include downstream markers of oxidative damage to macromolecules such as lipids, proteins and DNA. Oxidative stress is also indirectly assessed by estimating capacity for antioxidant defense in serum, or other body fluids. Such measures include assessment of enzymatic antioxidant activity and individual assessment of circulating non-enzymatic antioxidant levels [6].

Successful initiation of pregnancy requires the ovulation of a mature oocyte, production of competent sperm, proximity of sperm and oocyte in the reproductive

**183**

radical (OH·

*Antioxidant and Infertility*

fertility is shown in **Figure 1**.

pathological mechanisms [11].

electron in the outermost shell [4].

derived from nitrogen [13].

**2.2 Types of free radical species**

and reactive nitrogen species (NOS).

**2.3 Reactive oxygen species (ROS)**

**2.4 Reactive nitrogen species**

cells and tissues damage [16].

**2.1 Free radicals**

**2. Role of free radicals in unexplained infertility**

excess of free radical results in oxidative stress [14].

*DOI: http://dx.doi.org/10.5772/intechopen.95791*

tract, fertilization of the oocyte, transport of the conceptus into the uterus, and implantation of the embryo into a properly prepared, healthy endometrium. A dysfunction in any one of these complex biological steps can cause infertility [7]. Free radicals can affect the female fertility potential in number of ways which can contribute negatively to a number of reproductive processes including folliculogenesis, oocyte maturation, sperm DNA damage, necrozoospermia, asthenospermia, endometriosis [8]. High levels of ROS play an important role in the etiology of male and female infertility. It has been proposed that the imbalance between antioxidants and ROS, favoring the latter, is responsible for increased OS levels that induce infertility [9]. Fissore *et al* [10] have found that OS is associated with maternal aging and postovulatory aging of the ova. The Role of oxidative stress in

The role of Oxidative Stress in female reproductive diseases and infertility is under intense investigations [8]. Whenever there is imbalance in the levels of ROS and antioxidants, damage can occur to oocytes and embryos through various

A free radical is any atom (e.g. oxygen, nitrogen) with at least one unpaired

Free radical atoms are unstable and highly reactive. They become stable by acquiring electrons from nucleic acids, lipids, proteins, carbohydrates or any nearby molecule causing a cascade of chain reactions resulting in cellular damage and disease [5]. The terms free radical and ROS are commonly used in an interchangeable manner, despite the fact that not all ROS are free radicals [12]. For example, hydrogen peroxide (H2O2) is considered a ROS but it is not a free radical since it does not contain unpaired electrons. In addition, there is a sub-class of free radicals

There must be a balance between oxidants and antioxidants, generation of an

There are two major types of free radical species: reactive oxygen species (ROS)

The Oxygen centered free radicals are class of powerful oxidants in the human

The two common examples of reactive nitrogen species are nitric oxide (NO) and nitrogen dioxide (NO**2**). Nitric oxide is a highly reactive free radical results in

), singlet oxygen (1O**2**), and a number of related species, such as hydrogen peroxide (H**2**O**2**), that do not themselves contain unpaired electrons but

−

), the hydroxyl

body. The most common ROS include: the superoxide anion (O**<sup>2</sup>**

are often involved in the generation of free radicals [15].

#### *Antioxidant and Infertility DOI: http://dx.doi.org/10.5772/intechopen.95791*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

Empirical treatment with clomiphene,intrauterine insemination are used in treatment of unexplained infertility, if failed, invitro fertilization is considered. Because female ovary is the source of oocytes and regulating hormones, free radicals in the gynecologic environment is likely to be an important mediator of conception. Recently there is a growing evidence of possible role of highly reactive

A free radical is any atom (e.g. oxygen, nitrogen) with at least one unpaired electron in the outermost [4]. Free radicals are neutralized by an elaborate antioxidant defense system. In a healthy body, pro-oxidants and antioxidants maintain a ratio and a shift in this ratio towards pro-oxidants gives rise to oxidative stress [3]. In this case free radical species which are unstable and highly reactive, will become stable by acquiring electrons from nucleic acids, lipids, proteins, carbohydrates or any nearby molecule causing a cascade of chain reactions resulting in cellular damage and diseas [5]. Because free radicals are unstable, and difficult to measure, traditional indices of oxidative stress include downstream markers of oxidative damage to macromolecules such as lipids, proteins and DNA. Oxidative stress is also indirectly assessed by estimating capacity for antioxidant defense in serum, or other body fluids. Such measures include assessment of enzymatic antioxidant activity and individual assessment of circulating non-enzymatic antioxidant levels [6]. Successful initiation of pregnancy requires the ovulation of a mature oocyte, production of competent sperm, proximity of sperm and oocyte in the reproductive

products of oxygen, termed free radicals, in infertility [3].

**182**

**Figure 1.**

*Role of oxidative stress in fertility.*

tract, fertilization of the oocyte, transport of the conceptus into the uterus, and implantation of the embryo into a properly prepared, healthy endometrium. A dysfunction in any one of these complex biological steps can cause infertility [7].

Free radicals can affect the female fertility potential in number of ways which can contribute negatively to a number of reproductive processes including folliculogenesis, oocyte maturation, sperm DNA damage, necrozoospermia, asthenospermia, endometriosis [8]. High levels of ROS play an important role in the etiology of male and female infertility. It has been proposed that the imbalance between antioxidants and ROS, favoring the latter, is responsible for increased OS levels that induce infertility [9]. Fissore *et al* [10] have found that OS is associated with maternal aging and postovulatory aging of the ova. The Role of oxidative stress in fertility is shown in **Figure 1**.

The role of Oxidative Stress in female reproductive diseases and infertility is under intense investigations [8]. Whenever there is imbalance in the levels of ROS and antioxidants, damage can occur to oocytes and embryos through various pathological mechanisms [11].

## **2. Role of free radicals in unexplained infertility**

## **2.1 Free radicals**

A free radical is any atom (e.g. oxygen, nitrogen) with at least one unpaired electron in the outermost shell [4].

Free radical atoms are unstable and highly reactive. They become stable by acquiring electrons from nucleic acids, lipids, proteins, carbohydrates or any nearby molecule causing a cascade of chain reactions resulting in cellular damage and disease [5]. The terms free radical and ROS are commonly used in an interchangeable manner, despite the fact that not all ROS are free radicals [12]. For example, hydrogen peroxide (H2O2) is considered a ROS but it is not a free radical since it does not contain unpaired electrons. In addition, there is a sub-class of free radicals derived from nitrogen [13].

There must be a balance between oxidants and antioxidants, generation of an excess of free radical results in oxidative stress [14].

#### **2.2 Types of free radical species**

There are two major types of free radical species: reactive oxygen species (ROS) and reactive nitrogen species (NOS).

#### **2.3 Reactive oxygen species (ROS)**

The Oxygen centered free radicals are class of powerful oxidants in the human body. The most common ROS include: the superoxide anion (O**<sup>2</sup>** − ), the hydroxyl radical (OH· ), singlet oxygen (1O**2**), and a number of related species, such as hydrogen peroxide (H**2**O**2**), that do not themselves contain unpaired electrons but are often involved in the generation of free radicals [15].

#### **2.4 Reactive nitrogen species**

The two common examples of reactive nitrogen species are nitric oxide (NO) and nitrogen dioxide (NO**2**). Nitric oxide is a highly reactive free radical results in cells and tissues damage [16].

### **2.5 Sources of free radicals in human body**

The main four endogenous normal sources appear to account for most of the oxidants produced by cells; are aerobic respiration in mitochondria, Phagocyte, Peroxisomes and Cytochrome P450 enzymes. Exogenous sources may significantly increase the large endogenous oxidant load which include: Iron and copper salts [17]; smoking and alcohol; normal diets (fried food, caffien) [18]; radiation, sunlight; pollution and xenobiotics (Drugs,pesticides, anesthetics,andindustrial solvents) [19].

### **2.6 Pathological damage of free radicals**

Interaction of free radicals with other compounds results in a chain reactions of oxidation and reduction which ultimately can lead to cellulardamage [6].

Oxidation of DNA molecules, for example, can result in mutation where as oxidation of protein can result in protein cross-linking and loss function [20].

Reactive oxygen species can attack polyunsaturated fatty acids of the cell membrane leading to a chain of chemical reactions called lipid peroxidation and this will lead to decrease structural fluidity of these compounds, thus resulting in loss of integrity of cellular membranes [6]. It is possible to measure the extent of peroxidative damage by estimatingthe stable end products of lipid peroxidation such as MDA (malondiadehyde) [3].

#### **2.7 Types of antioxidants**

There are two types of antioxidants in the human body: enzymatic and non-enzymatic antioxidants [11]:

#### *2.7.1 Enzymatic antioxidants*

Enzymatic antioxidants are also known as natural antioxidants. They are mainly composed of:


Antioxidant enzymes may act in a coordinate manner to defend living tissue from oxidant [21].

Superoxide dismutase is a protein dimer,destroys the free radical superoxide by converting it to peroxide [22].

Catalase is a hemoprotein enzyme of the oxidoreductase class that catalyzes the convertion of hydrogen peroxide to water and oxygen, active H2O2 [23].

Glutathione peroxidase, is a tetramer protein containing selenium, and uses glutathione as a co-substrate. Glutathione peroxidase is a cytosolic enzyme and also eliminates H2O2; but, in comparison to catalase, has a wider range of substrates including lipid peroxides. Glutathione peroxidase primarily functions to detoxify low levels of H2O2 in the cell [24].

#### *2.7.2* **Non-enzymatic antioxidants**

Non-enzymatic antioxidants are also known as synthetic antioxidants or dietary supplements. The body's complex antioxidant system is influenced by dietary intake

**185**

*Antioxidant and Infertility*

*DOI: http://dx.doi.org/10.5772/intechopen.95791*

glutathione and beta carotene [11].

*2.7.2.1 Vitamin C (Ascorbic acid)*

many fruit and vegetable [25].

*2.7.2.2 Vitamin E*

glutathione [29].

substrate [32].

duction of ROS.

genetic alterations within cells [26, 27].

and has positive effects in the fertility [28].

accumulation of free radicals called antioxidants [30].

**2.8 Antioxidant defense system**

against free radical damage include:

• Prevention of formation of free radicals.

converting them to less reactive molecules.

of antioxidant vitamins and minerals such as vitamin C, vitamin E, selenium, zinc,

Vitamin C is a water soluble vitamin found in many fruit and vegetable. Vitamin C is required for optimal functions of number of enzymes;deficiency cause scurvy and poor wound repair. It is also considered a chain breaking antioxidant that stops the propagation of the peroxidative process. Vitamin C also helps recycle oxidized vitamin E and glutathione, It is an unstable,easily oxidized acid and can be destroyed by oxygen, alkaline and high temperature. Humans cannot synthesize vitamin C, so they take it from exogenous supplement or diet found in

Tocopherol and Glutathione (GSH),also rely on vitamin C for regeneration back

Vitamin E is the collective name for a set of at least eight related tocopherols and tocotrienols compounds with similar biological antioxidants activity. Vitamin E is the first line of defense against lipid peroxidation. Moreover, it plays a very important function in lending red blood cells flexibility as they make their way through the arterial network and helps prolong the life of erythrocytes, immune function,

Vitamin C regenerates Vitamin E and Vitamin C is,in turn by regenerated

Organisms have developed efficient protective mechanisms against excessive

Free radicals are neutralized by an elaborate antioxidant defense system. In a healthy body, pro-oxidants and antioxidants maintain a ratio and a shift in this ratio towards pro-oxidants gives rise to oxidative stress. Whenever ROS levels become pathologically elevated, antioxidants begin to work and help minimize the oxidative damage, repair it or prevent it [31]. An antioxidant can be defined as any substance that, when present at low concentration compared to those of an oxidizable substance, significantly delays or prevents the oxidation of that

Under normal conditions, antioxidants convert ROS to H2O to prevent overpro-

The different possible mechanisms by which antioxidants may offer protection

• Interception of free radicals by scavenging the reactive metabolites and

to their active isoforms. The relationship between vitamin C and Glutathione is unique. Vitamin C reduces GSH back to the active form. Once reduced, Glutathione will regenerate vitamin C from its oxidized state. Vitamin C protects the DNA of the cells from the damage caused by free radicals and mutagens. It prevents harmful of antioxidant vitamins and minerals such as vitamin C, vitamin E, selenium, zinc, glutathione and beta carotene [11].

## *2.7.2.1 Vitamin C (Ascorbic acid)*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**2.5 Sources of free radicals in human body**

**2.6 Pathological damage of free radicals**

such as MDA (malondiadehyde) [3].

non-enzymatic antioxidants [11]:

**2.7 Types of antioxidants**

*2.7.1 Enzymatic antioxidants*

• Superoxide dismutase.

• Glutathione peroxidase.

converting it to peroxide [22].

low levels of H2O2 in the cell [24].

*2.7.2* **Non-enzymatic antioxidants**

composed of:

• Catalase.

from oxidant [21].

The main four endogenous normal sources appear to account for most of the oxidants produced by cells; are aerobic respiration in mitochondria, Phagocyte, Peroxisomes and Cytochrome P450 enzymes. Exogenous sources may significantly increase the large endogenous oxidant load which include: Iron and copper salts [17]; smoking and alcohol; normal diets (fried food, caffien) [18]; radiation, sunlight; pollution and xenobiotics (Drugs,pesticides, anesthetics,andindustrial solvents) [19].

Interaction of free radicals with other compounds results in a chain reactions of

Oxidation of DNA molecules, for example, can result in mutation where as oxidation of protein can result in protein cross-linking and loss function [20]. Reactive oxygen species can attack polyunsaturated fatty acids of the cell membrane leading to a chain of chemical reactions called lipid peroxidation and this will lead to decrease structural fluidity of these compounds, thus resulting in loss of integrity of cellular membranes [6]. It is possible to measure the extent of peroxidative damage by estimatingthe stable end products of lipid peroxidation

There are two types of antioxidants in the human body: enzymatic and

Enzymatic antioxidants are also known as natural antioxidants. They are mainly

Antioxidant enzymes may act in a coordinate manner to defend living tissue

Superoxide dismutase is a protein dimer,destroys the free radical superoxide by

Catalase is a hemoprotein enzyme of the oxidoreductase class that catalyzes the

Non-enzymatic antioxidants are also known as synthetic antioxidants or dietary supplements. The body's complex antioxidant system is influenced by dietary intake

Glutathione peroxidase, is a tetramer protein containing selenium, and uses glutathione as a co-substrate. Glutathione peroxidase is a cytosolic enzyme and also eliminates H2O2; but, in comparison to catalase, has a wider range of substrates including lipid peroxides. Glutathione peroxidase primarily functions to detoxify

convertion of hydrogen peroxide to water and oxygen, active H2O2 [23].

oxidation and reduction which ultimately can lead to cellulardamage [6].

**184**

Vitamin C is a water soluble vitamin found in many fruit and vegetable.

Vitamin C is required for optimal functions of number of enzymes;deficiency cause scurvy and poor wound repair. It is also considered a chain breaking antioxidant that stops the propagation of the peroxidative process. Vitamin C also helps recycle oxidized vitamin E and glutathione, It is an unstable,easily oxidized acid and can be destroyed by oxygen, alkaline and high temperature. Humans cannot synthesize vitamin C, so they take it from exogenous supplement or diet found in many fruit and vegetable [25].

Tocopherol and Glutathione (GSH),also rely on vitamin C for regeneration back to their active isoforms. The relationship between vitamin C and Glutathione is unique. Vitamin C reduces GSH back to the active form. Once reduced, Glutathione will regenerate vitamin C from its oxidized state. Vitamin C protects the DNA of the cells from the damage caused by free radicals and mutagens. It prevents harmful genetic alterations within cells [26, 27].

## *2.7.2.2 Vitamin E*

Vitamin E is the collective name for a set of at least eight related tocopherols and tocotrienols compounds with similar biological antioxidants activity. Vitamin E is the first line of defense against lipid peroxidation. Moreover, it plays a very important function in lending red blood cells flexibility as they make their way through the arterial network and helps prolong the life of erythrocytes, immune function, and has positive effects in the fertility [28].

Vitamin C regenerates Vitamin E and Vitamin C is,in turn by regenerated glutathione [29].

## **2.8 Antioxidant defense system**

Organisms have developed efficient protective mechanisms against excessive accumulation of free radicals called antioxidants [30].

Free radicals are neutralized by an elaborate antioxidant defense system. In a healthy body, pro-oxidants and antioxidants maintain a ratio and a shift in this ratio towards pro-oxidants gives rise to oxidative stress. Whenever ROS levels become pathologically elevated, antioxidants begin to work and help minimize the oxidative damage, repair it or prevent it [31]. An antioxidant can be defined as any substance that, when present at low concentration compared to those of an oxidizable substance, significantly delays or prevents the oxidation of that substrate [32].

Under normal conditions, antioxidants convert ROS to H2O to prevent overproduction of ROS.

The different possible mechanisms by which antioxidants may offer protection against free radical damage include:


## **2.9 Oxidative stress in female reproduction**


## *2.9.1 Free radicals, antioxidants, and reproductive processes in women*

The production of a viable oocyte is modulated by a complex interaction of endocrine, paracrine and autocrine factors, leading to follicular maturation, granulosa cell maturation, ovulation and luteinization [36]. Elevated concentrations of ROS in these environments may have detrimental effects on the spermatozoa, oocytes, sperm oocyte interaction and embryos both in the Fallopian tube and the peritoneal cavity;therefore oxidative stress modulates a host of reproductive pathologies affecting natural fertility in a woman's life [37]. Free radicals plays a role in the physiology of ovarian function [36]. They may have a regulatory role in oocyte maturation, folliculogenesis, ovarian steroidogenesis and luteolysis. There is a delicate balance between ROS and antioxidant enzymes in the ovarian tissues [11]. Vitamin C deficiency characteristically produces ovarian atrophy and extensive follicular atresia [36]. Glutathione has been identified as critical for oocyte maturation and formation of the male sperm pronucleus (PN) [4]


**187**

**Figure 2.**

*Antioxidant and Infertility*

*DOI: http://dx.doi.org/10.5772/intechopen.95791*

• Oocytes are also rich in glutathione reductase [24].

corpus luteum and surrounding cells (**Figure 2**) [42].

ovarian steroidogenesis and germ cell function [43].

coincide with poor fertilization success rates [46].

results in lack of luteal support to pregnancy [37].

*Reactive oxygen species in folliculogenesis in women ovary [43].*

from the adenohypophysis [44].

• Glutathione peroxidase may also maintain low levels of free radicals inside the follicle and thus play an important role in gametogenesis and fertilization [11]. Glutathione is considered the major source of redox potential in the oocyte [14].

• Reactive oxygen species are produced during luteal regression [28]. Because the corpus luteum produces much of the progesterone; ROS are produced as a byproduct [28]. The detoxification of the produced ROS by GSH in conjunction with antioxidative enzymes would be particularly important for the

Reactive oxygen species may act as important mediators in hormone signaling,

Oxidative stress may affect theca-interstitial cells by inducing their proliferation and growth. Higher doses of Oxidative stress inhibited the proliferation of the theca-interstitial cells while antioxidants stimulate the release of gonadotrophins

Cells involved in steroidogenesis such as theca cells, granulosa lutein cells, and hilus cells show stronger oxidative enzyme activity [45]. Over-exposure of the ovary to H2O2 causes the LH receptor to uncouple from adenyle cyclase, thereby impairing protein synthesis and cholesterol utilization by mitochondria [28].

Data suggest that vitamin C has defined functions in hormone secretion, gamete

protection, and gonadal tissue remodeling [26]. Steroidogenesis appears to be ascorbate-dependent [27] and the reduced concentrations of antioxidants often

Reactive oxygen species therefore play a role in the formation of the corpus luteum and steroidogenesis. Imbalance in redox leading to luteal regression that

on smooth muscles and it has similar effects on tubular contractility. Deficiency of NO may lead to tubal motility dysfunction, resulting in retention of the ovum,

Endogenous NO system exists in the fallopian tubes [36]. NO has a relaxing effect

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**2.9 Oxidative stress in female reproduction**

even thereafter (i.e. menopause).

contrast, received relatively little attention [8].

antioxidants [33].

plasma [35].

• Facilitating the repair of damage caused by free radicals.

• Providing a favorable environment for effective functioning of other

• The presence of oxidant and antioxidant systems in various reproductive tissues has evoked great interest in the role of OS in human reproduction. The role of ROS and antioxidants in relation to female reproductive function has, in

• Oxidative stress influences the entire reproductive span of women's life and

• Free radicals appear to have a physiological role in female reproductive

*2.9.1 Free radicals, antioxidants, and reproductive processes in women*

system in many different processes such as: oocyte maturation, fertilization, luteal regression, endometrial shedding and progesterone production by the corpus luteum [34]. Protection from ROS is afforded by scavengers present in both male and female reproductive tract fluids, as well as in seminal

The production of a viable oocyte is modulated by a complex interaction of endocrine, paracrine and autocrine factors, leading to follicular maturation, granulosa cell maturation, ovulation and luteinization [36]. Elevated concentrations of ROS in these environments may have detrimental effects on the spermatozoa, oocytes, sperm oocyte interaction and embryos both in the Fallopian tube and the peritoneal cavity;therefore oxidative stress modulates a host of reproductive pathologies affecting natural fertility in a woman's life [37]. Free radicals plays a role in the physiology of ovarian function [36]. They may have a regulatory role in oocyte maturation, folliculogenesis, ovarian steroidogenesis and luteolysis. There is a delicate balance between ROS and antioxidant enzymes in the ovarian tissues [11]. Vitamin C deficiency characteristically produces ovarian atrophy and extensive follicular atresia [36]. Glutathione has been identified as critical for oocyte maturation and formation of the male sperm pronucleus

• Glutathione in mature oocytes is thought to be a highly relevant biochemical marker for the viability of mammalian oocytes [38]. Hence, Follicular ROS initiate apoptosis; whereas follicular Glutathione, in addition to FSH, protect against apoptosis in cultured pre-ovulatory rat follicles [39]. The secreted Glutathione would protect oocytes against excessively produced ROS that occurs during the ovulation, thus maintaining fertilization potency [40].

• [41] observe that integrity of the antioxidant defenses within the different stages of oocyte development may contribute significantly to the overall quality of the oocytes. One consequence of an excess of ROS in the ovary may be plasma membrane damage of the oocytes. The significance of such damage for

female fertility, however, is unknown.

**186**

(PN) [4]


Reactive oxygen species may act as important mediators in hormone signaling, ovarian steroidogenesis and germ cell function [43].

Oxidative stress may affect theca-interstitial cells by inducing their proliferation and growth. Higher doses of Oxidative stress inhibited the proliferation of the theca-interstitial cells while antioxidants stimulate the release of gonadotrophins from the adenohypophysis [44].

Cells involved in steroidogenesis such as theca cells, granulosa lutein cells, and hilus cells show stronger oxidative enzyme activity [45]. Over-exposure of the ovary to H2O2 causes the LH receptor to uncouple from adenyle cyclase, thereby impairing protein synthesis and cholesterol utilization by mitochondria [28].

Data suggest that vitamin C has defined functions in hormone secretion, gamete protection, and gonadal tissue remodeling [26]. Steroidogenesis appears to be ascorbate-dependent [27] and the reduced concentrations of antioxidants often coincide with poor fertilization success rates [46].

Reactive oxygen species therefore play a role in the formation of the corpus luteum and steroidogenesis. Imbalance in redox leading to luteal regression that results in lack of luteal support to pregnancy [37].

Endogenous NO system exists in the fallopian tubes [36]. NO has a relaxing effect on smooth muscles and it has similar effects on tubular contractility. Deficiency of NO may lead to tubal motility dysfunction, resulting in retention of the ovum,

delayed sperm transport and infertility. Increased NO levels in the fallopian tubes are cytotoxic to the invading microbes and also may be toxic to spermatozoa [11].

**In male, ROS cause infertility by two principal mechanisms**:


The percentage of sperm with DNA damage is negatively correlated with the fertilization rate [47]. Oocytes can repair DNA damage to some extent, but when the damage is severe, embryo death and miscarriages can occur.

The inability of sperm to fuse with an oocyte appears to be due to the effects of ROS on the sperm membrane. As a result of lipid peroxidation process, spermatozoa are unable to initiate the necessary biochemical reactions associated with acrosome reaction, zona pellucida binding and oocyte penetration [29].

In addition, ROS brings about changes in the endometrium that prepare it for implantation [36]. Nitric oxide functions as an important vasodilator, neurotransmitter, regulator of implantation [8] and may also contribute as an anti-platelet agent during implantation [48].

## **3. The effect of some factors on free radicals levels**

#### **3.1 Body weight**

The effects of body weight and weight change on OS have only recently been investigated. More studies on this topic are needed, since both inadequate and excessive energy intakes have been associated with reduced fertility among women [49].

Research has focused on the effects of energy intake on hormonal patterns and menstrual cycles, ovulatory dysfunction and later age at menarche have been associated with both low and high body mass index (BMI, calculated as kg/m<sup>2</sup> ), energy intake and high levels of physical activity [50].

#### **3.2 Age**

It has been suggested that the age-related decline in fertility is modulated by OS. Moreover, there is an age related decline in the number and quality of follicles in females [51].

Several studies have investigated if there is an age-associated increase in the generation of oxidants by mitochondria [11]. Free radical activity of human follicular fluid increases with age [10] as does apoptosis (programmed cell death) of human granulosa and cumulus cells [9]. Carbone,*et al*. [52] find that a reduction in the expression of glutathione and CAT activity is demonstrated in older women compared with young controls. Yeh et al. [53] show alterations in antioxidant defense with age. It is hypothesized that diminished antioxidant status may induce apoptosis during luteal regression and lead to decreased progesterone synthesis.

#### **3.3 Smoking**

Smoking is known to decrease fertility in women [51], likely through an increase in OS. A history of smoking is associated with high levels of oxidative stress [36].

**189**

**5. Conclusion**

*Antioxidant and Infertility*

*DOI: http://dx.doi.org/10.5772/intechopen.95791*

**4. Overcoming OS in female infertility**

advised to stop exposure to them.

The oxides of nitrogen (NO) in cigarette smoke damage macromolecules and deplete antioxidant. This is likely to contribute significantly to the pathology of smoking [11]. Dietary intakes of smokers; however, are different from non-smokers, confounding this relationship [11]. It is found that intrafollicular exposure to cigarette smoking metabolites was associated with a significant increase in follicular lipid peroxidation and decrease in the local antioxidative potential [3]. Smoking significantly reduced glutathione peroxidase concentration in the follicular fluid [24]. Consequently, OS imbalance may be responsible for impaired folliculogenesis in female smokers [43].

Oxidative stress can be overcome by reducing generation of ROS or increasing the amounts of antioxidants available [11]. So prior to the treatment of female infertility, ROS levels should be assessed. By estimating ROS levels, it may be possible to identify the causes of infertility, especially in cases of idiopathic infertility [43]. It is important to identify the source of increased ROS generation [3]. Patients with history of smoking should be advised to stop smoking. In addition, Any exposure to drugs, toxic substances and radiation should be checked and patients should be

Infections of the reproductive tract should be treated with appropriate antibiotics [11]. Initially, specific therapeutic options directed against the etiological cause of raised ROS should be tried [3]. After treating the primary cause, patients can be advised to take antioxidant supplementation. Antioxidants can be started directly when a specific etiology cannot be identified (unexplained infertility) [43]. Considerable interest has been generated in the use of antioxidants to overcome the adverse and pathological results of OS. Some studies that used nutritional supplements and antioxidants, like vitamin C supplementation to protect against ROS and OS. However, there is a lack of consensus on the type and dosage of antioxidants to be used [3]. In vivo antioxidants may be helpful in smoker infertile women [24]. A study, impact of a nutritional supplement, containing vitamin E, iron, zinc and selenium, is examined. The patients receiving the supplement experienced a significant increase in ovulation rates and pregnancy rates compared with the placebo group [28]. Indirect evidence of the importance of OS and its control with antioxidant intake is provided by studies that have shown that preconceptional multivitamin supplementation may enhance fertility, perhaps by increasing menstrual cycle regularity [44] or via prevention of ovulatory disorders [46]. In general, when supplemental vitamins C and E are given to older mice, the age-associated reduction in ovulation is partially prevented [51]. There is sufficient evidence to hypothesize that diet, particularly its constituent antioxidants, and OS may influ-

• Assessment of OS as a cause of unexplained female infertility must be carried

• There is inverse significant relationship between GSH level with age and dura-

out to discriminate OS infertility from other causes of infertility.

tion of infertility increment in patients with unexplained infertility.

• There is an inverse significant relationship between Vitamine C and age

ence the timing and maintenance of a viable pregnancy [4].

increment in patients with unexplained infertility.

#### *Antioxidant and Infertility DOI: http://dx.doi.org/10.5772/intechopen.95791*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

embryo [13].

agent during implantation [48].

**3.1 Body weight**

**3.2 Age**

females [51].

**3.3 Smoking**

delayed sperm transport and infertility. Increased NO levels in the fallopian tubes are

• Reactive oxygen species damage the sperm membrane which, in turn, reduces

• Damage sperm DNA, compromising the paternal genomic contribution to the

The percentage of sperm with DNA damage is negatively correlated with the fertilization rate [47]. Oocytes can repair DNA damage to some extent, but when

The inability of sperm to fuse with an oocyte appears to be due to the effects of ROS on the sperm membrane. As a result of lipid peroxidation process, spermatozoa are unable to initiate the necessary biochemical reactions associated with acrosome

In addition, ROS brings about changes in the endometrium that prepare it for implantation [36]. Nitric oxide functions as an important vasodilator, neurotransmitter, regulator of implantation [8] and may also contribute as an anti-platelet

The effects of body weight and weight change on OS have only recently been investigated. More studies on this topic are needed, since both inadequate and excessive energy intakes have been associated with reduced fertility among women [49]. Research has focused on the effects of energy intake on hormonal patterns and menstrual cycles, ovulatory dysfunction and later age at menarche have been asso-

It has been suggested that the age-related decline in fertility is modulated by OS. Moreover, there is an age related decline in the number and quality of follicles in

Several studies have investigated if there is an age-associated increase in the generation of oxidants by mitochondria [11]. Free radical activity of human follicular fluid increases with age [10] as does apoptosis (programmed cell death) of human granulosa and cumulus cells [9]. Carbone,*et al*. [52] find that a reduction in the expression of glutathione and CAT activity is demonstrated in older women compared with young controls. Yeh et al. [53] show alterations in antioxidant defense with age. It is hypothesized that diminished antioxidant status may induce apoptosis during luteal regression and lead to decreased progesterone synthesis.

Smoking is known to decrease fertility in women [51], likely through an increase in OS. A history of smoking is associated with high levels of oxidative stress [36].

), energy

ciated with both low and high body mass index (BMI, calculated as kg/m<sup>2</sup>

cytotoxic to the invading microbes and also may be toxic to spermatozoa [11]. **In male, ROS cause infertility by two principal mechanisms**:

the sperm's motility and ability to fuse with the oocyte.

the damage is severe, embryo death and miscarriages can occur.

reaction, zona pellucida binding and oocyte penetration [29].

**3. The effect of some factors on free radicals levels**

intake and high levels of physical activity [50].

**188**

The oxides of nitrogen (NO) in cigarette smoke damage macromolecules and deplete antioxidant. This is likely to contribute significantly to the pathology of smoking [11].

Dietary intakes of smokers; however, are different from non-smokers, confounding this relationship [11]. It is found that intrafollicular exposure to cigarette smoking metabolites was associated with a significant increase in follicular lipid peroxidation and decrease in the local antioxidative potential [3]. Smoking significantly reduced glutathione peroxidase concentration in the follicular fluid [24]. Consequently, OS imbalance may be responsible for impaired folliculogenesis in female smokers [43].

## **4. Overcoming OS in female infertility**

Oxidative stress can be overcome by reducing generation of ROS or increasing the amounts of antioxidants available [11]. So prior to the treatment of female infertility, ROS levels should be assessed. By estimating ROS levels, it may be possible to identify the causes of infertility, especially in cases of idiopathic infertility [43]. It is important to identify the source of increased ROS generation [3]. Patients with history of smoking should be advised to stop smoking. In addition, Any exposure to drugs, toxic substances and radiation should be checked and patients should be advised to stop exposure to them.

Infections of the reproductive tract should be treated with appropriate antibiotics [11]. Initially, specific therapeutic options directed against the etiological cause of raised ROS should be tried [3]. After treating the primary cause, patients can be advised to take antioxidant supplementation. Antioxidants can be started directly when a specific etiology cannot be identified (unexplained infertility) [43]. Considerable interest has been generated in the use of antioxidants to overcome the adverse and pathological results of OS. Some studies that used nutritional supplements and antioxidants, like vitamin C supplementation to protect against ROS and OS. However, there is a lack of consensus on the type and dosage of antioxidants to be used [3]. In vivo antioxidants may be helpful in smoker infertile women [24]. A study, impact of a nutritional supplement, containing vitamin E, iron, zinc and selenium, is examined. The patients receiving the supplement experienced a significant increase in ovulation rates and pregnancy rates compared with the placebo group [28]. Indirect evidence of the importance of OS and its control with antioxidant intake is provided by studies that have shown that preconceptional multivitamin supplementation may enhance fertility, perhaps by increasing menstrual cycle regularity [44] or via prevention of ovulatory disorders [46]. In general, when supplemental vitamins C and E are given to older mice, the age-associated reduction in ovulation is partially prevented [51]. There is sufficient evidence to hypothesize that diet, particularly its constituent antioxidants, and OS may influence the timing and maintenance of a viable pregnancy [4].

## **5. Conclusion**


*Antioxidants - Benefits, Sources, Mechanisms of Action*

## **Author details**

Huda Mahmood Shakir Department of Obstetrics and Gynaecology, Ibn Sina University for Medical and Pharmaceuticals Sciences, Iraq

\*Address all correspondence to: hudaalfatal2010@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**191**

(1)28-33.

*Antioxidant and Infertility*

**References**

*DOI: http://dx.doi.org/10.5772/intechopen.95791*

[1] Siristatidis ,C. and Bhattacharya,S. (2007). Unexplained infertility: does it really exist? Does it matter?. Human Reproduction J., 22(8)2084-2087.

[2] Smith,S.; Pfiefer, S.M. and Collins, J. (2003). Diagnosis and management of female infertility. J.A.M.A. ,290:17.

S.S.(2004).Role of free radicals in female reproductive diseases and assisted reproduction.Reproductive BioMedicine

J.; Blumberg ,J.

activation and postovulatory ageing.

[11] Agarwal, A., Gupta, S. and Sharma, R.(2005). Oxidative stress and its implications in female infertility - a clinician's perspective. Reprod. Biomed.

[12] Cheeseman ,K.H. and Slater, T.F. (1993). An introduction to free radical biochemistry. Med Bull , 49:481-493.

[13] Tremellen, J. (2008). Oxidative stress and male infertility—a clinical perspective .Hum. Reprod. J. ,

[14] Fujii, J.; Iuchi, Y. and Okada, F.(2005). Fundamental roles of reactive oxygen species and protective mechanisms in the female reproductive system. Reprod. Biol. Endocrinol.,

[15] Christophersen, A. G.; Jun, H.; Jŕgensen, K., and Skibsted, L. H. (1991). Photobleaching of astaxanthin and canthaxanthin: quantum-yields dependence of solvent, temperature, and wavelength of irradiation in relation to packageing and storage of carotenoid pigmented salmonoids. Z. Lebensm.

Unters. Forsch., 192:433-439

J Reprod Med, 46:887-891.

USA ,87: 7777-7781.

[16] Dong, M.; Shi, Y. and Cheng, Q. (2001). Increased nitric oxide in peritoneal fluid from women with idiopathic infertility and endometriosis.

[17] Lauffer, R. B. (1992). Iron and Human Disease. CRC, Boca Raton, FL.

[18] Ames, B. N.; Profet, M. and

Gold, L. S. (1990). Proc. Natl. Acad. Sci.

[19] Bruce, N. Mark, K. and Tory, M. (1993). Oxidants, antioxidants, and the degenerative diseases of aging(cancer/ mutation/endogenous DNA adducts/

Reproduction J., 124:745-754.

Online,11(5): 641-650

14(3):243-258.

3:43-53.

[3] Agarwal, A. and Allamaneni,

and Goldman ,M.(2008). Oxidative stress and antioxidants: exposure and impact on female fertility. Human Reproduction and Embryology J.

[5] Van Langendonckt, A.; Casanas-Roux, F.; Donnez, J.(2002). Oxidative stress and peritoneal endometriosis.

[6] Janiki,Dj.(2008).oxidative stress. pittsburgh mind body center.

[7] Goldman, M.B.; Missmer, S.A. and Barberi ,R.L. (2000). Infertility. In:Women and Helath . San Diego:

[8] Guerin, P.; El Mouatassim, S. and Menezo, Y. (2001). Oxidative stress and protection against reactive oxygen species in the pre-implantation embryo and its surroundings. Hum. Reprod.

[9] Savita, S. M.; Anitha, S. K.; Chaya ,S. D. and Bharati,A . (2009). Oxidative stress-mediated essential polyunsaturated fatty acid alterations in female infertility .Human Fertility,12

[10] Fissore, R. A.; Kurokawa, M.;Knott, J.; Zhang, M. and Smyth, J.( 2002). Mechanisms underlying oocyte

Fertil. Steril. J.,77:861-870.

Academic Press., 196-214.

Update, 7:175-189.

Online, 9:338-347.

[4] Ruder,E.; Hartman,

## **References**

*Antioxidants - Benefits, Sources, Mechanisms of Action*

**190**

**Author details**

Huda Mahmood Shakir

Pharmaceuticals Sciences, Iraq

provided the original work is properly cited.

Department of Obstetrics and Gynaecology, Ibn Sina University for Medical and

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: hudaalfatal2010@gmail.com

[1] Siristatidis ,C. and Bhattacharya,S. (2007). Unexplained infertility: does it really exist? Does it matter?. Human Reproduction J., 22(8)2084-2087.

[2] Smith,S.; Pfiefer, S.M. and Collins, J. (2003). Diagnosis and management of female infertility. J.A.M.A. ,290:17.

[3] Agarwal, A. and Allamaneni, S.S.(2004).Role of free radicals in female reproductive diseases and assisted reproduction.Reproductive BioMedicine Online, 9:338-347.

[4] Ruder,E.; Hartman, J.; Blumberg ,J. and Goldman ,M.(2008). Oxidative stress and antioxidants: exposure and impact on female fertility. Human Reproduction and Embryology J.

[5] Van Langendonckt, A.; Casanas-Roux, F.; Donnez, J.(2002). Oxidative stress and peritoneal endometriosis. Fertil. Steril. J.,77:861-870.

[6] Janiki,Dj.(2008).oxidative stress. pittsburgh mind body center.

[7] Goldman, M.B.; Missmer, S.A. and Barberi ,R.L. (2000). Infertility. In:Women and Helath . San Diego: Academic Press., 196-214.

[8] Guerin, P.; El Mouatassim, S. and Menezo, Y. (2001). Oxidative stress and protection against reactive oxygen species in the pre-implantation embryo and its surroundings. Hum. Reprod. Update, 7:175-189.

[9] Savita, S. M.; Anitha, S. K.; Chaya ,S. D. and Bharati,A . (2009). Oxidative stress-mediated essential polyunsaturated fatty acid alterations in female infertility .Human Fertility,12 (1)28-33.

[10] Fissore, R. A.; Kurokawa, M.;Knott, J.; Zhang, M. and Smyth, J.( 2002). Mechanisms underlying oocyte

activation and postovulatory ageing. Reproduction J., 124:745-754.

[11] Agarwal, A., Gupta, S. and Sharma, R.(2005). Oxidative stress and its implications in female infertility - a clinician's perspective. Reprod. Biomed. Online,11(5): 641-650

[12] Cheeseman ,K.H. and Slater, T.F. (1993). An introduction to free radical biochemistry. Med Bull , 49:481-493.

[13] Tremellen, J. (2008). Oxidative stress and male infertility—a clinical perspective .Hum. Reprod. J. , 14(3):243-258.

[14] Fujii, J.; Iuchi, Y. and Okada, F.(2005). Fundamental roles of reactive oxygen species and protective mechanisms in the female reproductive system. Reprod. Biol. Endocrinol., 3:43-53.

[15] Christophersen, A. G.; Jun, H.; Jŕgensen, K., and Skibsted, L. H. (1991). Photobleaching of astaxanthin and canthaxanthin: quantum-yields dependence of solvent, temperature, and wavelength of irradiation in relation to packageing and storage of carotenoid pigmented salmonoids. Z. Lebensm. Unters. Forsch., 192:433-439

[16] Dong, M.; Shi, Y. and Cheng, Q. (2001). Increased nitric oxide in peritoneal fluid from women with idiopathic infertility and endometriosis. J Reprod Med, 46:887-891.

[17] Lauffer, R. B. (1992). Iron and Human Disease. CRC, Boca Raton, FL.

[18] Ames, B. N.; Profet, M. and Gold, L. S. (1990). Proc. Natl. Acad. Sci. USA ,87: 7777-7781.

[19] Bruce, N. Mark, K. and Tory, M. (1993). Oxidants, antioxidants, and the degenerative diseases of aging(cancer/ mutation/endogenous DNA adducts/

oxygen radicals). Proc. Natl. Acad. Sci. USA, 90: 7915-7922.

[20] Bergamini, C.M.; Gambetti, S.; Dondi, A. and Cervellati, C.(2004). Oxygen, reactive oxygen species and tissue damage. Curr. Pharm. Des.,10: 1611-1626.

[21] Quinlan, T.; Spivack, S. and Mossman, B.T (1994). Regulation of Antioxidant Enzymes in Lung after Oxidant Injury. Environmental Health Perspectives, 102(2):77-81.

[22] Benov, L. and Fridovich, I. (1998). Growth in iron-enriched medium partially compensates Escherichia coli for the lack of manganese and iron superoxide dismutase. Bio.l Chem. J., 273: 10313-10316.

[23] Brioukhanov, A.; Netrusov, A. and Eggen, R. (2006). The catalase and superoxide dismutase genes are transcriptionally up-regulated upon oxidative stress in the strictly anaerobic archaeon Methanosarcina barkeri. Microbiology, 152: 1671-1677.

[24] Paszkowski, T.; Traub, A.I.; Robinson, S.Y. and McMaster, D. (1995). Selenium dependent glutathione peroxidase activity in human follicular fluid. Clin. Chim. Acta., 236: 173-180

[25] Eidan, B.; almukhtar, N.; Altemimmi, H. (2009), relashionship betwwen cervical and blood free radicals concentration in unexplained infertility.

[26] Franceschi, R.T. (1992). The role of ascorbic acid in mesenchymal differentiation. Nutr. Rev. , 50:65-70

[27] Tsuji, M.; Ito, Y.; Terada, N. and Mori H.(1989). Ovarian aromatase activity in scorbutic mutantrats unable to synthesize ascorbic acid. Acta. Endocrinol. (Copenh) , 121:595-602.

[28] Behrman, H.R.; Kodaman, P.H.; Preston, S.L. and Gao, S.(2001).

Oxidative stress and the ovary. J. of the Society for Gynecol. Investigation, 8: S40-42.

[29] Griveau, J.F and Le Lannou, D. (1997). Reactive oxygen species and human spermatozoa: physiology and pathology. Int. J. Androl., 20:61-69.

[30] Ebisch, I.M.; Thomas, C.M.; Peters, W.H.; Braat, D.D. and Steegers-Theunissen, R.P. (2007). The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum. Reprod. Update, 13:163-174.

[31] Zini, A.; Garrels, K. and Phang, D. (2000). Antioxidant activity in the semen of fertile and infertile men. Urology J.,55:922-6.

[32] Lunec, J. (1990). Review Article, Ann Clin. Biochem., 27:173.

[33] Battino, M.; Ferreiro, M.S.; Galalrdo, I. ; Newman, H.N. and Bullon, P.(2002).The antioxidant capacity of saliva. J. Clin. Periodontol., 29:189-194.

[34] Sugino, N.; Nakata, M. and Kashida, A.( 2000). Decreased superoxide dismutase expression and increased concentration of lipid peroxide and prostaglandin F2" in the deciduas of failed pregnancy. Mol. Hum. Reprod., 6(7): 642-647

[35] Urner, F.; and Sakkas, D. (2005). Involvement of the pentose phosphate pathway and redox regulation in fertilization in the mouse. Mol. Reprod. Dev., 70,494-503.

[36] Agarwal, A.; Saleh, R.A. and Bedaiwy, M.A.(2003).Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil. Steril. J., 79: 829-843.

[37] Agarwal, A; Gupta, S.; Malhotra, N.; Sharma, D. and Chandra, A. (2009). Oxidative Stress and its Role in Female

**193**

*Antioxidant and Infertility*

147-164.

64:106-112.

51:23-35.

*DOI: http://dx.doi.org/10.5772/intechopen.95791*

oxidative stress. Human Reproduction,

[45] Cohen, G.; Dembiec, D. and Marcus, J. (1970). Measurement of catalase activity. Analyt.Biochem., 34 :

[46] Paszkowski, T.; Clarke, R. and Hornstein, M. (2002). Smoking induces oxidative stress inside the Graafianfollicle. J. Obstet. Gynecol.

Reprod. Biol.,17(4):921-925

[47] Sun, J.G.; Jurisicova, A. and Casper, R.F.(1997). Detection of deoxyribonucleic acid fragmentation in human sperm: correlation with fertilization in vitro.Biol. Reprod.,

[48] Cameron, I.T. and Campbell, S.

[49] Allaire, C.(2006). Endometriosis and infertility. Reprod. Med. J.,

[50] De Souza, M.J. and Williams, .I. (2004). Physiological Aspects and Clinical Sequelae of Energy Deficiency and Hypoestrogenism in Exercising Women. Human Reproduction Update,

[51] Tarin, J.; Ten, J.; Vendrell, F.J.; de Oliveira, M.N. and Cano, A. (1998). Effects of maternal ageing and dietary antioxidant supplementation on ovulation, fertilisation and embryo development in vitro in the mouse. Reprod. Nutr. Dev. , 38:499-508.

[52] Carbone, M.C.; Tatone, C. and Monache, S.(2003). Antioxidant enzymatic defences in human follicular

fluid: characterization and agedependent changes. Hum. Reprod.,

(1998). Nitric oxide in the endometrium. European Society of Hum. Reprod. and Embryology,

19:1519-1524.

30-38.

56:602-607

4(5):565.

51:164-168.

10(5):433-448.

9:639-643.

Infertility and Assisted Reproduction: Clinical Implications. International Journal of Fertil. and Steril., 2( 4):

Zucker, R.M. and Perreault, S.D.(2003). Glutathione (GSH) concentrations vary with the cell cycle in maturing hamster oocytes, zygotes, and pre-implantation stage embryos. Mol. Reprod. Dev.,

[39] Turton. M. and Luderer. U. (2006). Opposing Effects of Glutathione Depletion and FSH on Reactive Oxygen Species and Apoptosis in Cultured Preovulatory Rat Follicles. Endocrinology, 147:1224-1236.

[40] Ikeda, S.; Kitagawa, M.; Imai, H. and Yamada, M.(2005). The roles of vitamin A for cytoplasmic maturation of bovine oocytes. J. Reprod. Dev.,

[41] Goto, T.; Jones, G.M.; Lolatgis, N.; Pera, M.F.; Trounson ,A.O. and Monk M.( 2002).Identification and characterisation of known and novel transcripts expressed during the final stages of human oocyte maturation.

[42] Tatemoto, H.; Sakuraim N. and Muto, N.(2000). Protection of porcine oocytes against apoptotic cell death caused by oxidative stress during In vitro maturation: role of cumulus cells. Biology of Reproduction ,63 805-810.

[43] Agarwal, A.; Gupta, S.; Sekhon, L.

Considerations in Female Reproductive Function and Assisted Reproduction: From Molecular Mechanisms to Health Implications. Antioxidants and redox

Mol. Reprod .Dev., 62:13-28.

and Shaha,R.(2008).Redox

signaling J., 10(8):1376-1396

[44] Duleba, A.J.; Foyouzi, N. and Karaca, M.(2004). Proliferation of ovarian theca-interstitial cells is modulated by antioxidants and

[38] Zuelke, K.A.; Jeffay, S.C.;

*Antioxidant and Infertility DOI: http://dx.doi.org/10.5772/intechopen.95791*

*Antioxidants - Benefits, Sources, Mechanisms of Action*

Oxidative stress and the ovary. J. of the Society for Gynecol. Investigation, 8:

[29] Griveau, J.F and Le Lannou, D. (1997). Reactive oxygen species and human spermatozoa: physiology and pathology. Int. J. Androl., 20:61-69.

[30] Ebisch, I.M.; Thomas, C.M.; Peters, W.H.; Braat, D.D. and Steegers-Theunissen, R.P. (2007). The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum. Reprod.

[31] Zini, A.; Garrels, K. and Phang, D. (2000). Antioxidant activity in the semen of fertile and infertile men.

[32] Lunec, J. (1990). Review Article,

Galalrdo, I. ; Newman, H.N. and Bullon, P.(2002).The antioxidant capacity of saliva. J. Clin. Periodontol., 29:189-194.

Ann Clin. Biochem., 27:173.

[33] Battino, M.; Ferreiro, M.S.;

[34] Sugino, N.; Nakata, M. and Kashida, A.( 2000). Decreased superoxide dismutase expression and increased concentration of lipid peroxide and prostaglandin F2" in the deciduas of failed pregnancy. Mol. Hum.

[35] Urner, F.; and Sakkas, D. (2005). Involvement of the pentose phosphate pathway and redox regulation in fertilization in the mouse. Mol. Reprod.

[36] Agarwal, A.; Saleh, R.A. and Bedaiwy, M.A.(2003).Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil. Steril. J.,

[37] Agarwal, A; Gupta, S.; Malhotra, N.; Sharma, D. and Chandra, A. (2009). Oxidative Stress and its Role in Female

Reprod., 6(7): 642-647

Dev., 70,494-503.

79: 829-843.

Update, 13:163-174.

Urology J.,55:922-6.

S40-42.

oxygen radicals). Proc. Natl. Acad. Sci.

[20] Bergamini, C.M.; Gambetti, S.; Dondi, A. and Cervellati, C.(2004). Oxygen, reactive oxygen species and tissue damage. Curr. Pharm. Des.,10:

[21] Quinlan, T.; Spivack, S. and Mossman, B.T (1994). Regulation of Antioxidant Enzymes in Lung after Oxidant Injury. Environmental Health

[22] Benov, L. and Fridovich, I. (1998). Growth in iron-enriched medium partially compensates Escherichia coli for the lack of manganese and iron superoxide dismutase. Bio.l Chem. J.,

[23] Brioukhanov, A.; Netrusov, A. and Eggen, R. (2006). The catalase and superoxide dismutase genes are transcriptionally up-regulated upon oxidative stress in the strictly anaerobic archaeon Methanosarcina barkeri. Microbiology, 152: 1671-1677.

[24] Paszkowski, T.; Traub, A.I.;

Selenium dependent glutathione peroxidase activity in human follicular fluid. Clin. Chim. Acta., 236: 173-180

[25] Eidan, B.; almukhtar, N.;

infertility.

Robinson, S.Y. and McMaster, D. (1995).

Altemimmi, H. (2009), relashionship betwwen cervical and blood free radicals concentration in unexplained

[26] Franceschi, R.T. (1992). The role of ascorbic acid in mesenchymal differentiation. Nutr. Rev. , 50:65-70

[27] Tsuji, M.; Ito, Y.; Terada, N. and Mori H.(1989). Ovarian aromatase activity in scorbutic mutantrats unable to synthesize ascorbic acid. Acta. Endocrinol. (Copenh) , 121:595-602.

[28] Behrman, H.R.; Kodaman, P.H.; Preston, S.L. and Gao, S.(2001).

Perspectives, 102(2):77-81.

273: 10313-10316.

USA, 90: 7915-7922.

1611-1626.

**192**

Infertility and Assisted Reproduction: Clinical Implications. International Journal of Fertil. and Steril., 2( 4): 147-164.

[38] Zuelke, K.A.; Jeffay, S.C.; Zucker, R.M. and Perreault, S.D.(2003). Glutathione (GSH) concentrations vary with the cell cycle in maturing hamster oocytes, zygotes, and pre-implantation stage embryos. Mol. Reprod. Dev., 64:106-112.

[39] Turton. M. and Luderer. U. (2006). Opposing Effects of Glutathione Depletion and FSH on Reactive Oxygen Species and Apoptosis in Cultured Preovulatory Rat Follicles. Endocrinology, 147:1224-1236.

[40] Ikeda, S.; Kitagawa, M.; Imai, H. and Yamada, M.(2005). The roles of vitamin A for cytoplasmic maturation of bovine oocytes. J. Reprod. Dev., 51:23-35.

[41] Goto, T.; Jones, G.M.; Lolatgis, N.; Pera, M.F.; Trounson ,A.O. and Monk M.( 2002).Identification and characterisation of known and novel transcripts expressed during the final stages of human oocyte maturation. Mol. Reprod .Dev., 62:13-28.

[42] Tatemoto, H.; Sakuraim N. and Muto, N.(2000). Protection of porcine oocytes against apoptotic cell death caused by oxidative stress during In vitro maturation: role of cumulus cells. Biology of Reproduction ,63 805-810.

[43] Agarwal, A.; Gupta, S.; Sekhon, L. and Shaha,R.(2008).Redox Considerations in Female Reproductive Function and Assisted Reproduction: From Molecular Mechanisms to Health Implications. Antioxidants and redox signaling J., 10(8):1376-1396

[44] Duleba, A.J.; Foyouzi, N. and Karaca, M.(2004). Proliferation of ovarian theca-interstitial cells is modulated by antioxidants and

oxidative stress. Human Reproduction, 19:1519-1524.

[45] Cohen, G.; Dembiec, D. and Marcus, J. (1970). Measurement of catalase activity. Analyt.Biochem., 34 : 30-38.

[46] Paszkowski, T.; Clarke, R. and Hornstein, M. (2002). Smoking induces oxidative stress inside the Graafianfollicle. J. Obstet. Gynecol. Reprod. Biol.,17(4):921-925

[47] Sun, J.G.; Jurisicova, A. and Casper, R.F.(1997). Detection of deoxyribonucleic acid fragmentation in human sperm: correlation with fertilization in vitro.Biol. Reprod., 56:602-607

[48] Cameron, I.T. and Campbell, S. (1998). Nitric oxide in the endometrium. European Society of Hum. Reprod. and Embryology, 4(5):565.

[49] Allaire, C.(2006). Endometriosis and infertility. Reprod. Med. J., 51:164-168.

[50] De Souza, M.J. and Williams, .I. (2004). Physiological Aspects and Clinical Sequelae of Energy Deficiency and Hypoestrogenism in Exercising Women. Human Reproduction Update, 10(5):433-448.

[51] Tarin, J.; Ten, J.; Vendrell, F.J.; de Oliveira, M.N. and Cano, A. (1998). Effects of maternal ageing and dietary antioxidant supplementation on ovulation, fertilisation and embryo development in vitro in the mouse. Reprod. Nutr. Dev. , 38:499-508.

[52] Carbone, M.C.; Tatone, C. and Monache, S.(2003). Antioxidant enzymatic defences in human follicular fluid: characterization and agedependent changes. Hum. Reprod., 9:639-643.

*Antioxidants - Benefits, Sources, Mechanisms of Action*

[53] Yeh, J.; Bowman, M.J.; Browne, R.W. and Chen, N. 2005. Reproductive aging results in a reconfigured ovarian antioxidant defense profile in rats. Fertil. Steril. J.; 84(2):1109-1113.

**195**

Section 2

Antioxidant Compounds

Section 2
