**3. Diet and cancer**

Cancer is a multi stage process composed of complex stages in which gene expression, protein and metabolite function operate aberrantly [19]. Inherited mutations in genes can increase one's susceptibility for cancer; while the risk of developing cancer can be increased markedly, if there is a gene-diet interaction [19, 20]. Epigenetic functions has reversible nature which made them attractive as targets for drug development. Epigenome is continuously changing due to environmental factors such as diet, and lifestyle factors such as stress and exercise. Diet has been demonstrated to have important impact on epigenetic mechanisms [19–21]. Changes in dietary intake have been shown to affect epigenetic functions providing a significant reduction in cancer risk and also contributing to disease prevention [19–21]. In addition, revision of diet in cancer patients has shown to be resulted in changes in gene expression, that can enhance therapeutic efficacy. Diets rich in fish, fibers, fruits, vegetables, and reduction in consummation of red meat have affected the epigenome, providing therapeutic efficacy [21].

The impact of diet and environment on human health has been known since ages. Diet can either be a source of carcinogens present in certain foods or a source of protective contituents (vitamins, antioxidants, detoxifying enzyme-activating substances, etc.) [22]. Cancer initiation and progression have been linked to oxidative stress by DNA mutations, genome instability, and cell proliferation; therefore antioxidant agents could interfere with carcinogenesis. Natural herbs have been used for prevention or treatment of diverse diseases for thousands of years; depending on the presence of bioactive components in plants that makes them appropriate choices to be used as food or medicinal purposes. Plant derived bioactive components confirmed the anticancer activities of natural dietary phytochemicals which resulted in an increase in comprehension of these compounds as a biological functional agent which has a theuropetic effect on human health [22]. Epidemiological studies reported that diet rich in fruits and vegetables have cancer preventive properties and several phytochemicals originated of edible plants have defensive mechanisms that prevent the induction of carcinogenesis by scavenging free radicals and by transducting signals in response to stress factors that activate proteins associated to cellular signaling pathways [22]; thus, dietary phytochemicals are able to be a chemopreventative agent toward cancer by inflection of the cancer cell cycle, proliferation inhibition, and initiation of apoptosis [22, 23].

Common dietary compunds can act on the human genome, directly or indirectly, by altering gene expression or structure; some dietary constituents affect post translation events [23]. Acetylation of histones and non-histone proteins has been shown to affect cell metabolism and can be targeted by inhibitors of histone deacetylases (HDACs) and histone acetyl transferases (HATs) [23, 24]. Natural compounds from broccoli, garlic, curcumin speculated to have inhibitory effects of HDACs and HATs with their influence on epigenetic mechanisms for normalization of the deregulated cancer cell metabolism [23, 24]. Dietary factors can also interact with hormonal regulation such as obesity that strongly affects hormonal status such as phytoestrogens [23, 24].

Plant-derived natural bioactive compounds (phytochemicals) have acquired an important role in human diet as potent antioxidants and cancer chemopreventive agents [ 23 , 24 ]. Recently, the role of epigenetic alterations such as histone modifications, DNA methylation, and non-coding RNAs in the regulation of genome have been addressed ( **Figure 4** ) [ 25 ].

 The present review outlines epigenetic mechanisms in the regulation of genome and the role of dietary phytochemicals as epigenetic modifiers in cancer; summarizing the progress made in cancer chemoprevention with dietary phytochemicals, and the challenges in the future.

### **3.1 Cancer control and prevention by diet and epigenetic approaches**

 Epigenetic mechanisms are known to be essential for normal development and maintenance of adult life. Disruption of epigenetic processes results in deregulated gene expression and leads to life-threatening diseases, in particular, cancer, which is defined as both a genetic and epigenetic disease. Genetic and epigenetic events are suggested to be susceptible to environmental and lifestyle factors such as radiation, toxins, pollutants, infectious agents, and diet ( **Figures 5** and **6** ) [ 26 , 27 ], that affect the phenotype of cells and organisms. Diet is defined as more easily studied and therefore better understood environmental factor in epigenetic changes [ 26 , 27 ].

 Cancer is known to take many years to develop from initiation to progression, as the long period of development may represent an opportunity to use multi-functional preventive drugs to block or reverse tumorigenesis. Unlike genetic mutations, epigenetic alterations are potentially reversible and can be restored to their normal state, thus one path to cancer prevention can be to target and reverse these epigenetic defects. According to epidemiological studies there is a close link between rich diets in bioactive compounds and the low incidence of different types of cancer; regarding the impact of bioactive nutrients on the epigenetic mechanisms of gene expression, such as genomic DNA methylation, altered activity and expression of DNA methyl transferases and ten-eleven translocation enzymes, local DNA hypermethylation of gene promoters of tumor suppressor genes or of non-coding RNAs (microRNAs and long-noncoding RNAs), as well as global hypomethylation ( **Figures 5** and **6** ) [ 26 , 27 ].

### **Figure 4.**

 *Plant-derived natural bioactive compounds (phytochemicals) have acquired an important role in human diet as potent epigenetic modulators such as histone modifications, DNA methylation, and non-coding RNAs in the regulation of genome (from Daniele Segnini) [ 25 ].* 

*Diet-Epigenome Interactions: Epi-Drugs Modulating the Epigenetic Machinery during Cancer… DOI: http://dx.doi.org/10.5772/intechopen.95374*

### **Figure 5.**

*Epigenetic events are suggested to be susceptible to environmental and lifestyle factors such as radiation, toxins, pollutants, infectious agents, and diet [26].*

### **Figure 6.**

*Modulation and interaction of epigenetic mechanisms [27].*

Dietary components play importent roles in either cancer prevention or cancer development [28–31]. Intake of certain bioactive food components such as resveratrol (grapes), polyphenol-catechins (green tea), genistein (soybean), curcumin (turmeric), sulforaphane (cruciferous vegetables), and other bioactive components such as isothiocyanate (cruciferous vegetables), apigenin (parsley), silymarin (milk thistle), cyanidins (grapes), and rosmarinic acid (rosemary) (**Figure 7**) [28] is identified to play significant roles in modulating tumor risk and development [28–31].

Despite the investigations that epigenetic changes are heritable in somatic cells and epimutations are rare in healthy tissues, it is of interest to note that epigenetic modulations are potentially reversible. Depending on this property targeting epigenetic mechanisms have been a promising approach for cancer prevention [32]. Interestingly, altered diet is found to have transgenerational effects [33]. In a study done by Heijmans *et al.* [33] pregnant mothers during the Dutch Hunger Winter of

### **Figure 7.**

*Certain bioactive food components such as resveratrol (grapes), polyphenol-catechins (green tea), genistein (soybean), curcumin (turmeric), sulforaphane (cruciferous vegetables), and other bioactive components such as isothiocyanate (cruciferous vegetables) playing significant roles in modulating tumor risk and development [28].*

1944 to 1945; methylation profiles of the mothers' offspring six decades later are followed and compared them with the profiles of their unexposed, same-sex siblings. The data indicated hypomethylation of insulin-like growth factor 2 (*IGF2*) and hypermethylation of interleukin-10 (*IL-10*), *LEP*, *ABCA1*, and *MEGF*; indicating the significance of diet components in the development of diseases including cancer [34].

Several diet components are demonstrated to alter tumor cell behavior and cancer risk by influencing key pathways and steps in carcinogenesis, including inflammation, cell signaling, cell cycle control, hormonal regulation, apoptosis, differentiation, and carcinogen metabolism [31–34]. While, antioxidant compunds such as polyphenols and resveratrol, are known to modulate proliferating cell nuclear antigen, *p21*, and *p27* [34, 35]; and indole-3-carbinol inhibiting cellular proliferation in human breast cancer cells [34, 35]; xenobiotic compounds, such as tobacco-specific carcinogens known to induce lung cancer [36].

Epigenetic modifications such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs are the most common epigenetic mechanisms. Dietary agents such as sulforaphane (SFN) found in cruciferous plants and epigallocatechin-3-gallate (EGCG) in green tea are demonstrated to exhibit various epigenetic mechanisms such as histone modifications via histone deacetylase (HDAC), histone acetyltransferase (HAT) inhibition, DNA methyltransferase (DNMT) inhibition, or noncoding RNA expression [37, 38]. These phytochemicals are shown to have an enhanced effect on epigenetic changes, which play a crucial role in cancer prevention [37, 38]. Meanwhile, restriction of glucose has been suggested to decrease the incidence of cancer and diabetes. Diet rich in compounds such as SFN and EGCG are reported to modulate the epigenome positively and lead to many health benefits; while reducing glucose in the diet is conferred to reduced cancer incidence [37, 38]. As a result, due to change in lifestyle and food habits, people can reduce risk of diet-related diseases and cancers. This review is focused on the phytochemicals that can affect various epigenetic modifications such as DNA methylation and histone modifications as well as regulation of non-coding miRNAs expression for treatment and prevention of various types of cancer.

*Diet-Epigenome Interactions: Epi-Drugs Modulating the Epigenetic Machinery during Cancer… DOI: http://dx.doi.org/10.5772/intechopen.95374*

### **3.2 Dietary compounds as epigenetic modulating agents in cancer**

Drugs targeting epigenetic processes are called "epi-drugs", which are mostly plantderived compounds that work through epigenetic mechanisms such as polyphenols, alkaloids, organosulfur compounds, and terpenoids [39]. Epigenetic mechanisms such as DNA methylation and posttranslational histone modifications regulate expression of various genes of changes in the DNA sequence, that play important roles in controlling cellular functions, including the cell cycle, signal transduction and immunoresponses [40]. On the other hand, epigenetic aberrations are associated with proliferation of cancer cells and oncogenesis, that these epigenetic alterations have been identified in many human cancer cells [40, 41]. This review focuses on the plant-derived anticancer drugs with epigenetic mechanisms of action, and their potential use in epigenetic therapy.

### *3.2.1 Therapeutic potential of polyphenols on DNA methylation*

Plant-derived flavonoids as a therapeutic agents for cancer, attributed to their ability for epigenetic regulation of cancer pathogenesis [42]. The epigenetic mechanisms of various classes of flavonoids including flavonols, flavones, isoflavones, flavanones, flavan-3-ols, and anthocyanidins, such as cyanidin, delphinidin, and pelargonidin, are demonstrated [43]. These phytochemicals are mainly contained in fruits, vegetables and seeds, as well as in dietary supplements; that act as powerful antioxidants and anticarcinogen agents; such as curcumin, catechins, genistein, quercetin and resveratrol.

As known, epigenetic modifications of chromatin are reversible and inherited, so they represent promising targets for the development of novel drugs targeting the epigenome which can contribute to amelioration of conventional therapies in cancer [44]. It has been reported that a diet rich in phytochemicals may act through epigenetic mechanisms such as modulation of DNMTs and HDACs activities that can significantly reduce the risk of cancer development by regulating the expression of oncogenes and tumor suppressor genes [45]. Cancer treatments are involved using chemo-radio therapeutic agents, kinase inhibitors, antibodies as well as certain compounds that stimulate the immune system, generally. Meanwhile, demethylating drugs modified gene expressions by reversing the aberrant epigenetic alterations acquired during tumorigenesis [44, 45]. In this context, polyphenolic flavonoid compounds may represent an alternative therapeutic option for cancer treatment.

Flavonoids are natural phenolic molecules that form a large group of secondary plant metabolites with important biological activities; subgroups of flavonoids are: flavonols such as quercetin, kaempferol, and myricetin; that are found in onions, curly, broccoli. The flavanones as hesperetin and naringenin that are found in grapefruit, oranges, and lemons. Isoflavonoids including daidzein and genistein are found in leguminous. The flavones as apigenin and luteolin that are present in cereals. The flavanols as catechin are found in green tea and chocolate, and the anthocyanins including cyanidin, delphinidin, malvidin, pelargonidin, peonidin, and petunidin are present in berries, pears, apples, grapes and peaches [46]. The biological effects of flavonoids have been linked to their antioxidative activities, that these compounds inhibit cell proliferation, induce cytotoxicity, suppression of angiogenesis; and situmulation of apoptosis, in cancer (**Figure 8**) [27]; displaying diverse properties affecting epigenetic mechanisms such as modulation of the DNA methylation and histone acetylation [23–25].

Phytochemicals and other bioactive dietary compounds are reported to restore global and gene-specific promoter DNA methylation patterns by reactivating

### **Figure 8.**

*Epigenetic machinery that is included the regulation of DNMTs and HDACs activities [27] (from Jan Frank).*

DNA methyltransferases or by providing the provision of methyl groups [47]. This review focuses on the impact of modified DNA methylation pattern on early carcinogenesis and summarizes the effects/mechanism of phytochemical interventions on this type of epigenetic alterations. Recent investigations reported that flavonoids blocked the development and progression of tumors by targeting key signaling transducers resulting in the restoration of tumor suppressor genes, and inhibition of oncogenes expression [44–47] by modulating epigenetic machinery that is included the regulation of DNMTs and HDACs activities (**Figure 8**) [27].

Depending on epidemiological studies, dietary flavonoid intake is strongly suggested to reduce the risk of numerous cancer entities. According to current studies, cancer is preventable with appropriate or balanced diet and avoidance of obesity [48–50], in some cases. Multiple biologically active food components are strongly suggested to have protective potential against cancer formation, examples are methylgroup donors such as phytochemicals, flavonoids, isothiocyanates, allyl compounds, selenium and fatty acids [49–51].

### *3.2.1.1 Epigenetic effects of curcumin in cancer prevention*

The yellow pigment curcumin (diferuloyl methane), a polyphenolic compound derived from turmeric (*Curcuma longa* Linn), a major ingredient of the spice curry, possessing remarkable antioxidant properties and has been studied for its potential anti-anticancer effects [52]. It has a broad spectrum of activities and acts on signaling pathways, particularly NF-B signaling; has been shown to induce apoptosis and block invasion, metastasis, and angiogenesis for all major tumor entities [52]. It has been reported to modulate epigenetic changes in cancer cells, and has been shown to be a DNA hypomethylation agent in colon, prostate, and breast cancer, thus serving as a chemopreventive agent [53], other epigenetic studies include histone acetylation/ deacetylation, and histone methylation/demethylation [52, 53]. Curcumin is first identified as an inhibitor of HAT activity; as a specific inhibitor of p300, also identified as inhibitor of acetylation of the tumor suppressor protein p53 as a non-histone protein target of p300 [52, 53], considering acetylation of p53 to be essential for

*Diet-Epigenome Interactions: Epi-Drugs Modulating the Epigenetic Machinery during Cancer… DOI: http://dx.doi.org/10.5772/intechopen.95374*

p53-dependent growth arrest and apoptosis; curcumin and its derivatives have also been identified as potent modulators of miRNAs [53].

## *3.2.1.2 Epigenetic effects of isothiocyanates in cancer prevention*

Organosulfur compounds, isothiocyanates (ITCs), are the most investigated glucosinolate-derived bioactive diet components. The chemopreventive properties of ITCs on cancer, are well demonstrated [18, 38, 54]. Although the anticancer effects of ITCs, little attention has focused on their ability about the epigenetic processes that lead to epigenetic changes in cancer. Regular intake of organosulfur compounds is reported to protect cardiovascular health [18, 38, 54], besides prevent carcinogenesis stimulated by N-nitrosodiethylamine [18, 38, 54].

### *3.2.1.3 Epigenetic effects of green tea polyphenols in cancer prevention*

Green tea polyphenols constitute a mixture of flavan-3-ols containing a catechol moiety. Biochemical compounds from green tea such as (−)-epigallocatechin gallate have been demonstrated to alter DNA methyltransferase activity in studies of various cancer cells. Mouse model studies have confirmed the inhibitory effect of (−)-epigallocatechin gallate on DNA methylation [27, 55].

### *3.2.1.4 Epigenetic effects of quercetin in cancer prevention*

Quercetin is reported to have a broad spectrum of cancer-preventive activities: acting as an antioxidant and modulating enzymes and signaling cascades involved in detoxification, inflammation, proliferation, apoptosis, angiogenesis, autophagy, immune defense, and senescence; besides it has been suggested to have potential to inhibit DNMT activity *in vitro*, associated with p16 up-regulation at the mRNA and protein level and inhibition of cell proliferation [27, 56].

### *3.2.1.5 Epigenetic effects of resveratrol in cancer prevention*

Resveratrol is a plant-derived stilbene derivative found in fruits, especially in the skin of red grapes [45]. It has been reported to have a broad spectrum of healthbeneficial effects, including antioxidant, cardioprotective, and antitumor activities, which have mechanistically been linked to effects on cell signaling related to cell survival, apoptosis, inflammation and tumor angiogenesis [45, 46]. Resveratrol was shown to prevent carcinogenesis in animal models for various cancer typesi, and reduced xenograft growth of various tumor cell lines. For example, activation of the aryl hydrocarbon receptor (AhR) has been shown to lead to epigenetic silencing of the DNA repair gene BRCA1 in breast cancer [57–59].

### *3.2.1.6 Epigenetic effects of anacardic acid in cancer prevention*

A component of cashew nut shell liquid, anacardic acid (6-nonadecyl salicylic acid), is identified as a natural-product inhibitor of the HAT enzyme which is involved in the activation of key enzymes of DNA damage response, which is also found to inhibit p300-mediatedacetylation of the p65 subunit of NF-B (nuclear factor "kappa light-chain enhancer" of activated B cells) as a non-histone substrate of HATs, and inhibited NF-B-mediated signaling involved in inflammation, cell survival, proliferation, and invasion [60–62].

### *3.2.1.7 Epigenetic effects of gallic acid in cancer prevention*

Gallic acid (3,4,5-trihydroxybenzoic acid), having high antioxidant activity is found in various fruit, tea and coffee, witch hazel, sumach, oak bark, walnuts, berries and other plants, as free tannins and as part of hydrolyzable tannins (gallotannins) [63]; has been shown to reduce oxidative DNA damage and to induce apoptosis in cancer cells [64]. It is identified as a specific inhibitör of HAT activity *in vitro*, and finally reduced NF-B activation and expression of anti-apoptotic genes in response to pro-inflammatory stimuli [64].

### *3.2.1.8 Epigenetic effects of delphinidin in cancer prevention*

Fruit, particularly blueberries contain anthocyanidins that have high antioxidant potential; possessing antiproliferative activity, inducing apoptosis and cell differentiation, and inhibiting angiogenesis and invasiveness, contributing to their high chemopreventive potential [60, 61, 65]. Overall, anthocyanidins have been shown to prevent cancer, and delphinidin has been identified as a HAT inhibitor [65]. HATmediated acetylation of histones and non-histone proteins seems to play an important role and; as gallic acid, delphinidin is proved to reduce pro-inflammatory signaling by preventing acetylation of the NF-B [65], contributing to the anti-inflammatory activity of chemopreventive polyphenols [65].

### *3.2.1.9 Epigenetic effects of flavolignan silymarin in cancer prevention*

Milk thistle (*Silybum marianum*) is used to protect liver against various diseases, and poisions. Silymarin is derived from milk-thistle seeds contains at least seven flavolignans and additional components. The most abundant compound is silybinin (or silibinin), existing as isomers, silybin A and B. Cancer-preventive potential of milk-thistle has been attributed to the inhibition of cell growth, angiogenesis, tumor invasion, metastasis, and inflammation [66, 67]. It is reported that silybinin treatment reduced the growth of human liver cancer xenografts through induction of apoptosis, and this was associated with an increase in histone H3 and H4 acetylation [68].

### *3.2.1.10 Epigenetic effects of genistein and soy isoflavones in cancer prevention*

Isoflavones (genistein and daidzein) are a class of flavonoids found in plants of the *Fabaceae* family abundantly, and characterized by phytoestrogenic properties. They are contained in high amounts in soybean (*Glycine max* L.) and are enriched in soy products. Epidemiological studies indicates an inverse correlation between a traditional soy-rich, low-fat Asian diet and the risk of developing breast and prostate cancer [69, 70]. As soy isoflavones and phytoestrogens bind to the estrogen receptor and modulate ER signaling; genistein has been shown to affect several additional chemopreventive mechanisms, including inhibition of oxidative stress, activation of carcinogens, cell signaling, angiogenesis, modulation of cell-cycle regulation, induction of apoptosis and inhibition of inflammation [71]. Recent investigations of a growth-promoting effect of genistein in ER-positive breast-cancer cell lines and xenograft models have indicated a potential risk of genistein for human health [72]; while another recent review does not support these concerns that genistein is tested in various clinical trials for the treatment and prevention of prostate, bladder, kidney, breast, and endometrial cancer [73]. Nutrients are classified that supply methyl
