**5. Antioxidants as a double-edged sword in cancer**

Antioxidants as chemicals that interact with neutralized free radicals can prevent them from causing damages. Antioxidants divide to two main subgroups including enzymatic and nonenzymatic antioxidants. Catalase, superoxide dismutase, and glutathione peroxidases are some of the most important enzymatic antioxidants [11]. Catalase (EC 1.11.1.6) as the first antioxidant enzyme was to be characterized and catalyzes conversion of hydrogen peroxide to water and oxygen. Superoxide dismutase (EC 1.15.1.1) is one of the most potent intracellular enzymatic antioxidants that catalyzes the conversion of superoxide anions to dioxygen and hydrogen peroxide. Glutathione peroxidases catalyze the oxidation of glutathione

at the direction of a hydroperoxide, which may be hydrogen peroxide or another species such as a lipid hydroperoxide.

Also, flavonoids, alkaloids, coumarins, carotenoids, and vitamins such as E, A, C (ascorbic acid), and D3 are some of the most important nonenzymatic antioxidants that are usually available in many natural products [24].

Antioxidants are known as free radical scavengers. Examples of dietary antioxidants include beta-carotene, lycopene, and vitamins A, C, and E (alphatocopherol). Also, the mineral element selenium is often thought to be a dietary antioxidant. Moreover, natural compounds such as flavonoids, in particular ECGC and resveratrol, were shown to have a promising future as antioxidants and anticarcinogenic agents. These compounds can be consumed through fruits and vegetables [25]. In recent years, potential chemotherapeutic properties of antioxidants have been evaluated as a primary agent or in combination with an already established chemotherapeutic agent for different types of cancers. There is friction among researchers about the efficacy and safety of these complimentary treatments and their substantial role in protecting tumor cells from conventional therapy. The antioxidants can be endogenous or obtained exogenously as a part of a diet or as dietary supplements [11].

However, many natural compounds such as natural antioxidants display opposing properties in cancer cells, depending on their concentration (**Figure 2**). Some recent studies imply that much of late-stage cancer's incurability may be due to its possession of too many antioxidants [14]. Actually, antioxidants may also cause direct damage to DNA and the cell. Watson recently wrote that time has come to seriously ask whether antioxidant use predominately causes rather than prevents cancer [26].

**177**

dant network."

*Antioxidants as a Double-Edged Sword in the Treatment of Cancer*

such as polyphenols are significant groups of Nrf2 inhibitors.

inhibit antioxidant defense and induce oxidative stress.

**6. Antioxidants and tumorigenesis**

Some of these studies proposed that in some cases high-dose supplements of antioxidants may be related to health hazards. For example, high doses of betacarotene may enhance the risk of lung cancer in smokers. Prostate cancer can occur in dealing with high doses of vitamin E [27]. Antioxidant supplements may also interact with some medications. Based on these new concepts, the continuous use of certain antioxidants such as glutathione, superoxide dismutase, catalase, and thioredoxin may serve as a barrier to apoptosis, the main anticancer mechanism,

The excessive damages via ROS can be associated with changes in mitochondrial membrane permeability, which result in cytochrome C release and apoptotic death. Against, cancer cells boost their anti-apoptotic mechanisms like a nuclear factor kappa-light-chain-enhancer of activated B cell (NFĸB) pathway to escape cell death [9]. Disruption of redox balance in cells causes activation of the transcription factors like nuclear factor erythroid 2-related factor 2 (Nrf2), NFĸB, and activator protein 1 (AP-1) as redox-sensitive transcription factors [28]**.** Nrf2 transcription factor is the major driver of antioxidant expression that leads to protection against DNA damage, endogenous and exogenous hazards, and consequent cancer initiation [29, 30]. Nrf2 overexpresses in some types of human cancers including skin, head, and neck, squamous cell carcinoma, esophagus, pancreatic, gallbladder, prostate, colorectal, breast, lung, and ovary. The cytoprotective properties of the Nrf2 indicate that this pathway can be exploited by tumor cells to promote their survival [31, 32]. In the ROS-sensitive cancer cells, natural product-derived inhibitors of Nrf2 pathway can induce ROS that may result in cell death [28]. Many antioxidants

Particularly in the case of cancer, the Nrf2 pathway has opposing properties: activating the pathway is vital for chemoprevention, but when the control is lost, it provides big consequences, so cancer cells result in fast proliferation, the escape of senescence and apoptosis, and resistance to chemotherapy and radiotherapy. Therefore, both activation and inhibition of Nrf2 activities can be beneficial [33]. As said above, natural products with antioxidant agents target Nrf2 pathway as an anticancer approach [28]. Several antioxidants may interact with other antioxidants that regenerate their primary properties; this mechanism is known as the "antioxi-

Opposing activities of natural products such as antioxidants in prevention and treatment of cancer depend on their concentration. At lower amounts, they often promote cells' antioxidant capacity via activating Nrf2-dependent signaling and enhancing expression of ROS scavengers. However, higher concentrations can

Genetic alterations that promote tumor cause to produce endogenous antioxidants [14]. In this process, Nrf2 is the main factor for the transactivation of involved genes in the maintenance of redox homeostasis [34]. As constitutive upregulation of Nrf2 factor has been reported for a variety of human cancer types, Nrf2 activity has been indicated to be necessary for proliferation of cancer cells [35–37], reprogramming of metabolism [38], chemoresistance [39], serine biosynthesis [36], as well as mRNA translation [37] in part through maintenance of redox homeostasis. Hi-activated pathway of Nrf2 increases the amount of cellular ROS scavengers. On the other hand, lowering stress burden via enhancing detoxifying force can affect the pathways that promote proliferation and growth [40, 41]. Blocking antioxidant activity in cancer cells decreases their ability to balance oxidative insult and might

*DOI: http://dx.doi.org/10.5772/intechopen.85468*

through excessively reducing ROS [11].

**Figure 2.** *Natural antioxidants act as a double-edged sword in cancer [28].*

#### *Antioxidants as a Double-Edged Sword in the Treatment of Cancer DOI: http://dx.doi.org/10.5772/intechopen.85468*

*Antioxidants*

species such as a lipid hydroperoxide.

dietary supplements [11].

cancer [26].

that are usually available in many natural products [24].

at the direction of a hydroperoxide, which may be hydrogen peroxide or another

Antioxidants are known as free radical scavengers. Examples of dietary antioxidants include beta-carotene, lycopene, and vitamins A, C, and E (alphatocopherol). Also, the mineral element selenium is often thought to be a dietary antioxidant. Moreover, natural compounds such as flavonoids, in particular ECGC and resveratrol, were shown to have a promising future as antioxidants and anticarcinogenic agents. These compounds can be consumed through fruits and vegetables [25]. In recent years, potential chemotherapeutic properties of antioxidants have been evaluated as a primary agent or in combination with an already established chemotherapeutic agent for different types of cancers. There is friction among researchers about the efficacy and safety of these complimentary treatments and their substantial role in protecting tumor cells from conventional therapy. The antioxidants can be endogenous or obtained exogenously as a part of a diet or as

Also, flavonoids, alkaloids, coumarins, carotenoids, and vitamins such as E, A, C (ascorbic acid), and D3 are some of the most important nonenzymatic antioxidants

However, many natural compounds such as natural antioxidants display opposing properties in cancer cells, depending on their concentration (**Figure 2**). Some recent studies imply that much of late-stage cancer's incurability may be due to its possession of too many antioxidants [14]. Actually, antioxidants may also cause direct damage to DNA and the cell. Watson recently wrote that time has come to seriously ask whether antioxidant use predominately causes rather than prevents

**176**

**Figure 2.**

*Natural antioxidants act as a double-edged sword in cancer [28].*

Some of these studies proposed that in some cases high-dose supplements of antioxidants may be related to health hazards. For example, high doses of betacarotene may enhance the risk of lung cancer in smokers. Prostate cancer can occur in dealing with high doses of vitamin E [27]. Antioxidant supplements may also interact with some medications. Based on these new concepts, the continuous use of certain antioxidants such as glutathione, superoxide dismutase, catalase, and thioredoxin may serve as a barrier to apoptosis, the main anticancer mechanism, through excessively reducing ROS [11].

The excessive damages via ROS can be associated with changes in mitochondrial membrane permeability, which result in cytochrome C release and apoptotic death. Against, cancer cells boost their anti-apoptotic mechanisms like a nuclear factor kappa-light-chain-enhancer of activated B cell (NFĸB) pathway to escape cell death [9]. Disruption of redox balance in cells causes activation of the transcription factors like nuclear factor erythroid 2-related factor 2 (Nrf2), NFĸB, and activator protein 1 (AP-1) as redox-sensitive transcription factors [28]**.** Nrf2 transcription factor is the major driver of antioxidant expression that leads to protection against DNA damage, endogenous and exogenous hazards, and consequent cancer initiation [29, 30]. Nrf2 overexpresses in some types of human cancers including skin, head, and neck, squamous cell carcinoma, esophagus, pancreatic, gallbladder, prostate, colorectal, breast, lung, and ovary. The cytoprotective properties of the Nrf2 indicate that this pathway can be exploited by tumor cells to promote their survival [31, 32]. In the ROS-sensitive cancer cells, natural product-derived inhibitors of Nrf2 pathway can induce ROS that may result in cell death [28]. Many antioxidants such as polyphenols are significant groups of Nrf2 inhibitors.

Particularly in the case of cancer, the Nrf2 pathway has opposing properties: activating the pathway is vital for chemoprevention, but when the control is lost, it provides big consequences, so cancer cells result in fast proliferation, the escape of senescence and apoptosis, and resistance to chemotherapy and radiotherapy. Therefore, both activation and inhibition of Nrf2 activities can be beneficial [33]. As said above, natural products with antioxidant agents target Nrf2 pathway as an anticancer approach [28]. Several antioxidants may interact with other antioxidants that regenerate their primary properties; this mechanism is known as the "antioxidant network."

Opposing activities of natural products such as antioxidants in prevention and treatment of cancer depend on their concentration. At lower amounts, they often promote cells' antioxidant capacity via activating Nrf2-dependent signaling and enhancing expression of ROS scavengers. However, higher concentrations can inhibit antioxidant defense and induce oxidative stress.
