Increased Antioxidant Capacity and Genomic Stability

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The traits described thus far are acquired in the course of tumor progression via alterations in the genomes of cancer cells, resulting from DNA damage. Cells are exposed to a variety of oxidizing agents, termed reactive oxygen species (ROS), coming from exogenous and endogenous sources that can damage DNA. Oxidative damage of DNA, if left unrepaired, can lead to base mutations, single and double strand breaks, DNA cross-linking, chromosomal breaks and rearrange-ments.50 An estimate of the daily rate of oxidative damage to DNA is 104 hits per cell in humans.51 Normally there is a balance between oxidizing and antiox-idizing molecules in the body and mutations in specific genes are kept in check by a number of DNA monitoring and repair systems that work to prevent and reverse alterations in specific genes.50 However, an imbalance in the system due to overproduction of free radical oxidants or an inadequacy of antioxidants, can lead to oxidative damage of large biomolecules, including DNA, proteins, and lipids.52 As described above, DNA damage activates p53 tumor suppressor protein to arrest the cell cycle to allow DNA repair or induce apoptosis when damage is too excessive.

Antioxidants common in fruits and vegetables can either prevent formation of, scavenge, or promote decomposition of ROS.51 Classical antioxidant nutrients include vitamins E and C, P-carotene, and selenium. However, a large number of phytochemicals can accumulate within cells and act as either antioxidants or even pro-oxidants. Vegetables and fruits are rich in polyphenols such as epigal-locatechin gallate, quercetin, genistein, and taxifolin, which are excellent anti-oxidants in vitro.52 The relationship between high consumption of antioxidants from fruits and vegetables and risk of a variety of cancer sites, including lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas, and ovary, has been reviewed.53 However, although vegetable and fruit intake can be approximated using current databases, total antioxidant activity is more difficult to determine due to large differences in antioxidant capabilities between plants and their edible parts, and even within a plant food due to agronomy and post-harvest conditions.52 Wu et al. surveyed more than 100 different kinds of foods (also assessing variation due to geographic region, season, and processing), including fruits, vegetables, nuts, dried fruits, spices, cereals, infant food, and other foods for hydrophilic and lipophilic antioxidant capacities to arrive at a total antioxidant capacity.54 These types of data are important for databases, which can be used to evaluate total antioxidant intake from nutrient as well as "nonnu-trient" antioxidants and relate it to cancer risk. These data can be used to show an inverse correlation between total antioxidant capacity intake and risk of cancer, as was done recently for gastric cancer.55

2.5.8 Other Mechanisms

The above analysis, focusing on the six essential alterations in cell physiology as defined by Hanahan and Weinberg26 and their modification by nutrients, focuses mainly on the changes within the cancer cells themselves. However, the effects of nutrients on other aspects affecting cancer incidence and progression at the tissue and whole-body levels cannot be ignored. Some of these other factors include effects on inflammation, carcinogen detoxification by xenobiotic metabolizing enzymes, and epigenetic events.

2.5.8.1 Inflammation

Prostaglandins and other members of the eicosanoid pathway are thought to induce carcinogenesis through action on nuclear transcription sites and downstream gene products important in the control of cell proliferation. Eicosanoids are locally acting hormone-like compounds derived predominantly from arachi-donic acid in tissue cells and tumor-infiltrating leukocytes.56 The most well-known eicosanoids, prostaglandins, are produced by the action of the cyclooxygenases (COX), but the lipoxygenase group of enzymes produce the leukotrienes and hydroperoxyeicosatetraenoic acids, which also have important proinflammatory effects.57 Substantial evidence from animal studies and human epidemiological and clinical trials show that nonsteroidal anti-inflammatory drugs (NSAIDs), which are inhibitors of COX, are associated with reduced risk of a number of cancers, including those of the colon-rectum, esophagus, stomach, pancreas, breast, lung, prostate, bladder, brain, and cervix.57

However, chronic NSAID use leads to toxicities, including gastric ulceration, perforation, or obstruction, which limit their therapeutic use.57 Newer selective COX-2 inhibitors have been postulated to be safer, but the recent voluntary worldwide recall of Merck's product Vioxx® (rofecoxib) — and subsequently other NSAIDs — illustrates that the long-term safety of these drugs has yet to be established.58 Therefore, research has focused on identifying and understanding the bioactivity of a number of natural, nontoxic agents to control inflammatory eicosanoids. Those agents that have been studied include n-3 polyunsaturated fatty acids EPA and DHA such as from fish oils, vitamin A, vitamin E, and a number of botanical anti-inflammatory agents, such as boswellia, bromelain, curcumin, resveratrol, quercetin, EGCG, and others.57 One mechanism of action of these compounds is via inhibition of the inducible transcription factor nuclear factor kappa B (NF-kB), which is activated by pro-inflammatory signals and upregulates COX-2 expression.59

2.5.8.2 Carcinogen Activation/Detoxification by Xenobiotic Metabolizing Enzymes

Although this discussion has focused on the beneficial roles of certain dietary constituents, we must recognize the role of dietary carcinogens as well. A number of known or suspected dietary carcinogens are present in foods, including myc-otoxins (moldy foods), polycyclic aromatic hydrocarbons and heterocyclic amines (grilled, fried, broiled, or charred meats and fish), N-nitrosoamines (foods preserved with nitrates and nitrites), alcohol (alcoholic beverages), as well as certain metals and pesticides.60 The enzymes responsible for the oxidation, reduction, and conjugation of harmful and other dietary constituents, as well as endogenous hormones and other foreign compounds, are called drug metabolizing enzymes (DMEs). The Phase I enzymes, which include the cytochrome P450 mixed-function oxidases, act by oxidizing, reducing, or hydrolyzing toxins, creating biotransformed intermediates. This process exists in the cell to detoxify compounds by rendering them more water soluble for excretion in the urine. However, as a consequence certain foreign compounds, termed xenobiotics, can be activated to increase their mutagenicity in the process. Phase II enzymes perform conjugation reactions that help to convert the biotransformed intermediates from Phase I into less-toxic, water-soluble substances for excretion from the body. These enzymes may also work independently of Phase I activity by acting directly on a drug or toxin. Phase II enzymes include glutathione-S-transferases (GSTs), UDP-glucuronosyl transferases, and quinone reductase. Phase I enzyme activity must be in balance with that of Phase II for effective elimination of biotransformed intermediates to prevent accumulation of toxins in the body. Another potentially damaging effect of the Phase I enzymes is the production of oxygen free radicals that occur as a result of cytochrome P450 activity.61 Oxidative stress in the liver is prevented by adequate intake of antioxidants, such as vitamins C and E, and many naturally occurring phytochemicals can also act as antioxidants, as reviewed above.

Vegetables of the Brassica oleracea species (e.g., cabbage, broccoli, cauliflower, Brussels sprouts, kohlrabi, and kale; also called cruciferous vegetables) as well as many other genera that include a variety of food plants (e.g., arugula, radish, daikon, watercress, horseradish, and wasabi) are known to be rich in glucosinolates (P-thioglycoside-N-hydroxysulfates). These compounds are hydrolyzed by myrosinase, a plant enzyme released when plants are cut, ground, or chewed, releasing the biologically active isothiocyanates (ITC). Some naturally occurring forms of this phytochemical include 2-phenethyl isothiocyanate, benzyl isothiocyanate, and sulforaphanes.62 ITCs are known to induce expression of Phase I and Phase II enzymes and, to a lesser extent, also directly inhibit the P450s; the effect is dependent on the individual ITC. However, in animal models and cell culture systems, combinations of ITC confer protection against genotoxic agents at levels that the individual compounds do not achieve alone.63 A number of human epidemiological studies have shown an inverse relationship between cruciferous vegetable intake and risk of cancer. Importantly, this effect is dependent on individual polymorphisms in the biotransformation enzyme genes. The relationship with GST has been most studied. For example, in a case-control study, Lin et al. showed that individuals with the highest quartile of broccoli intake had the lowest risk for colorectal adenomas compared with individuals who never ate broccoli, but the effect was seen only in the GSTMl-null (an inactivating mutation in a GST class ^ isozyme) genotype individuals.64 This genetic polymorphism is theorized to result in longer circulating half-lives of ITC and potentially greater chemoprotective effects by activation of other GST enzymes.

2.5.8.3 Epigenetic Events

Much of the previous discussion has focused on genomic alterations by dietary constituents. However, a key role of nutrient action is epigenetic, referring to changes in the phenotype that are not due to changes in the genotype, or in other words, changes in gene expression that are transmissible through mitosis, but do not involve mutations of the primary DNA sequence itself.65

A critical mechanism for epigenetic gene regulation involves alterations in patterns of DNA methylation. DNA methylation, or the covalent addition of a methyl group to the 5-position of cytosine within CpG dinucleotides, is particularly important in epigenetic control by nutrients. Tumors commonly exhibit widespread global DNA hypomethylation, region-specific hypermethylation, and increased activity of Dnmt enzymes, which catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to cytosine residues in DNA. Global genomic hypomethylation is linked to induction of chromosomal instability while hyper-methylation is associated with inactivation of most pathways of carcinogenesis, including DNA repair, cell cycle regulation, and apoptosis.66

Dietary factors may influence DNA methylation patterns in several ways. First, nutrient inadequacies will influence the supply of methyl groups for the formation of SAM. Dietary factors that are involved in one-carbon metabolism that influence the availability of SAM include folate, vitamin B12 (cobalamin), vitamin B6 (pyroxidine), vitamin B2 (riboflavin), methionine, choline, and alcohol. Other nutrients including zinc, selenium, and retinoic acid will affect global DNA hypomethylation.66 A second way is by altering the use of methyl groups, including altering DNA methyltransferase activity via Dnmt enzymes. Higher Dnmt activity has been observed in tumor cells compared to normal cells, and activity of these enzymes is upregulated with chronic methyl deficiency, in an apparent attempt to compensate for diminished SAM supply. In addition the DNA deme-thylation process, previously assumed to be passive, may be a regulated activity.66 These changes in methylation patterns can influence activity of specific genes; this likely occurs through modifying transcription factor-gene interactions through methyl-DNA binding proteins.66 For example, consumption of a chronic methyl-deficient diet in rats leads to hepatomas.67 In this model, hypomethylation of specific CpG sites in several oncogenes, including c-myc, c-fos, and H-ras, results in elevated mRNA levels for these genes.6869 Also, in the same model, levels of p53 tumor suppressor mRNA is decreased in tumor tissue due to relative hypermethylation, although the level of p53 mRNA in preneoplastic nodules was increased and associated with hypomethylation in the coding region.70

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