Protective role of Apigenin on the status of lipid peroxidation and antioxidant defense against hepatocarcinogenesis in Wistar albino rats.

Apigenin, a dietary plant derived flavone subclass of flavonoid is expected to play a role in cancer chemoprevention and cancer chemotherapy. Here we designed our experiment to establish whether treatment of apigenin (25 mg/kg body weight) for 14 consecutive days to (N-nitrosodiethylamine) DEN induced (200 mg/kg body weight; by single ip. injection) and phenobarbital promoted (0.05% through drinking water for 14 successive weeks) rats provide protection against the oxidative stress caused by the carcinogen. The level of lipid peroxidation (LPO) markedly increased in carcinogen administered animals, which was brought back to near normal by apigenin treatment. In contrast the activities/levels of the antioxidant status both in liver and kidney were decreased in carcinogen administered animals, which was recouped back to near normal upon apigenin administration. From our findings we concluded that apigenin prevents LPO and protects antioxidant system in DEN induced and phenobarbital promoted hepatocellular carcinogenesis.     

Are the recommended allowances for dietary antioxidants adequate?

Recommended dietary allowances are standards for maintaining health. Claims that intakes substantially above the allowances may provide protection from xenobiotics and prevent diseases, including cancer, are examined critically for five nutrients that have antioxidant potential. Major criticism is directed at the failure of epidemiologists to recognize that for many of these nutrients, metabolic differences among individuals preclude a direct relationship between dietary intake and plasma or tissue concentration. Also, the fact that no differences in disease incidence have been described within various species of animals that have markedly different metabolic patterns for some of these nutrients has not been considered. It is concluded that the experimental and epidemiological evidence to data that increased intakes of certain nutrients will have beneficial effects on human health are tenuous.     

Dietary pattern analysis: a new direction in nutritional epidemiology.

Recently, dietary pattern analysis has emerged as an alternative and complementary approach to examining the relationship between diet and the risk of chronic diseases. Instead of looking at individual nutrients or foods, pattern analysis examines the effects of overall diet. Conceptually, dietary patterns represent a broader picture of food and nutrient consumption, and may thus be more predictive of disease risk than individual foods or nutrients. Several studies have suggested that dietary patterns derived from factor or cluster analysis predict disease risk or mortality. In addition, there is growing interest in using dietary quality indices to evaluate whether adherence to a certain dietary pattern (e.g. Mediterranean pattern) or current dietary guidelines lowers the risk of disease. In this review, we describe the rationale for studying dietary patterns, and discuss quantitative methods for analysing dietary patterns and their reproducibility and validity, and the available evidence regarding the relationship between major dietary patterns and the risk of cardiovascular disease.     

Methyl-donor nutrients inhibit breast cancer cell growth

Lipotropes (methyl group containing nutrients, including methionine, choline, folate, and vitamin B(12)) are dietary methyl donors and cofactors that are involved in one-carbon metabolism, which is important for genomic DNA methylation reactions and nucleic acid synthesis. One-carbon metabolism provides methyl groups for all biological methylation pathways and is highly dependent on dietary supplementation of methyl nutrients. Nutrition is an important determinant of breast cancer risk and tumor behavior, and dietary intervention may be an effective approach to prevent breast cancer. Apoptosis is important for the regulation of homeostasis and tumorigenesis. The anti-apoptotic protein Bcl-2 may be a regulatory target in cancer therapy; controlling or modulating its expression may be a therapeutic strategy against breast cancer. In this study, the effects of lipotrope supplementation on the growth and death of human breast cancer cell lines T47D and MCF-7 were examined and found to inhibit growth of both T47D and MCF-7 cells. Furthermore, the ratios of apoptotic cells to the total number of cells were approximately 44% and 34% higher in the lipotrope-supplemented treatments of T47D and MCF-7 cancer cells, respectively, compared with the control treatments. More importantly, Bcl-2 protein expression was decreased by approximately 25% from lipotrope supplementation in T47D cells, suggesting that lipotropes can induce breast cancer cell death by direct downregulation of Bcl-2 protein expression. Cancer treatment failure is often correlated with Bcl-2 protein upregulation. These data may be useful in the development of effective nutritional strategies to prevent and reduce breast cancer in humans.     

DHA Supplemented in Peptamen Diet Offers No Advantage in Pathways to Amyloidosis: Is It Time to Evaluate Composite Lipid Diet?

Numerous reports have documented the beneficial effects of dietary docosahexaenoic acid (DHA) on beta-amyloid production and Alzheimer's disease (AD). However, none of these studies have examined and compared DHA, in combination with other dietary nutrients, for its effects on plaque pathogenesis. Potential interactions of DHA with other dietary nutrients and fatty acids are conventionally ignored. Here we investigated DHA with two dietary regimes; peptamen (pep+DHA) and low fat diet (low fat+DHA). Peptamen base liquid diet is a standard sole-source nutrition for patients with gastrointestinal dysfunction. Here we demonstrate that a robust AD transgenic mouse model shows an increased tendency to produce beta-amyloid peptides and amyloid plaques when fed a pep+DHA diet. The increase in beta-amyloid peptides was due to an elevated trend in the levels of beta-secretase amyloid precursor protein (APP) cleaving enzyme (BACE), the proteolytic C-terminal fragment beta of APP and reduced levels of insulin degrading enzyme that endoproteolyse beta-amyloid. On the contrary, TgCRND8 mice on low fat+DHA diet (based on an approximately 18% reduction of fat intake) ameliorate the production of abeta peptides and consequently amyloid plaques. Our work not only demonstrates that DHA when taken with peptamen may have a tendency to confer a detrimental affect on the amyloid plaque build up but also reinforces the importance of studying composite lipids or nutrients rather than single lipids or nutrients for their effects on pathways important to plaque development.     

Dietary factors and growth and metabolism in experimental tumors

Development of a diet that provides adequate nutrition and effective cancer prevention is an important goal in nutrition and cancer research. A confounding aspect of dietary control of tumor growth is the fact that some nutrients may up-regulate tumor growth, whereas other nutrients and nonnutrients down-regulate growth. Both up- and down-regulators may be present in the same foodstuff. Identification of these substances, determination of their mechanisms of action and potencies, as well as the interactions among the different mechanisms are topics of ongoing research. In this review, we describe results obtained in vivo or during perfusion in situ using solid tissue-isolated rodent tumors and human cancer xenografts in nude rats. Linoleic acid (LA), an essential n-6 polyunsaturated fatty acid (PUFA), was identified as an agent in dietary fat that is responsible for an up-regulation of tumor growth in vivo. Tumor LA uptake, mediated by high intratumor cAMP, stimulated formation of the mitogen, 13-hydroxyoctadecadienoic acid (13-HODE) and also increased ERK1/2 phosphorylation, [(3)H]thymidine incorporation and growth. A mechanism for control of this growth-promoting pathway was revealed during studies of the effects of dietary nutrients and nonnutrients known to inhibit tumor growth. These included four groups of lipophilic agents: n-3 fatty acids, melatonin, conjugated LA isomers and trans fatty acids. Each of these agents activated an inhibitory G protein-coupled receptor-mediated pathway that specifically suppressed tumor uptake of saturated, monounsaturated and n-6 PUFAs, thereby inhibiting an early step in the LA-dependent growth-promoting pathway.     

Signal transduction pathways leading to cell cycle arrest and apoptosis induction in cancer cells by Allium vegetable-derived organosulfur compounds: a review

Epidemiological studies continue to support the premise that dietary intake of Allium vegetables (e.g., garlic, onions and so forth) may lower the risk of various types of cancer. Anticarcinogenic effect of Allium vegetables is attributed to organosulfur compounds (OSCs) that are generated upon processing of these vegetables. Preclinical studies have provided convincing evidence to indicate that Allium vegetable-derived OSCs including diallyl sulfide, diallyl disulfide and diallyl trisulfide are highly effective in affording protection against cancer in laboratory animals induced by a variety of chemical carcinogens. Inhibition of carcinogen activation through modulation of cytochrome P450-dependent monooxygenases and/or acceleration of carcinogen detoxification via induction of phase II enzymes (glutathione transferases, quinone reductase, etc.) are believed to be responsible for protective effects of OSCs against chemically induced cancers. More recent studies have indicated that some naturally occurring OSC analogues can suppress proliferation of cancer cells in culture and inhibit growth of transplanted tumor xenografts in vivo by inducing apoptosis and/or by perturbing cell cycle progression. This review summarizes current knowledge on signal transduction pathways leading to perturbations in cell cycle progression and apoptosis induction by OSCs.     

The lipidome as a composite biomarker of the modifiable part of the risk of breast cancer

The potential for dietary fat to prevent breast cancer makes identification of defined molecules a mandatory step. In order to circumvent the limitations and/or bias of dietary exposure assessment tools, we have used the fatty acid composition of white adipose tissue as biomarker of past lipid intake. When considered separately, candidate fatty acids identified as favourable on the basis of their association with breast cancer risk have usually led to inconsistent results in dietary intervention studies carried out in rats. This inconsistency indicates that any approach based on a single fatty acid should be abandoned for an integrated view over the complex lipid interactions, which finally determines the lipidome, the lipid profile that is found in individuals. We reappraised the role of the complete lipid profile through a comprehensive study of adipose tissue fatty acids obtained in patients with benign or malignant breast tumors. Rather than a single fatty acid, a composite indicator combining elevated monounsaturates and low n-6/n-3 fatty acid ratio was associated with decreased breast cancer risk. The lipidome may provide the opportunity to quantify the modifiable part of the risk of breast cancer. The lipidome may be used as a template for designing proper dietary modifications in order to delay the occurrence of breast cancer. Which dietary modifications should be undertaken in order to bring a pertinent change to the lipidome with respect to the risk of breast cancer is currently unknown. The lipidome may allow the individualization of a high risk population of women, who may be targeted for a dietary prevention of breast cancer. The setting and validation of a high-throughput lipidomic station with analytical capabilities fitted to the need of mass screening is required. These two locks must be resolved before a primary prevention of breast cancer by diet could be contemplated.     

Beta-carotene: a cancer chemopreventive agent or a co-carcinogen?

Evidence from both epidemiological and experimental observations have fueled the belief that the high consumption of fruits and vegetables rich in carotenoids may help prevent cancer and heart disease in humans. Because of its well-documented antioxidant and antigenotoxic properties, the carotenoid beta-carotene (betaCT) gained most of the attention in the early 1980s and became one of the most extensively studied cancer chemopreventive agents in population-based trials supported by the National Cancer Institute. However, the results of three randomized lung cancer chemoprevention trials on betaCT supplementation unexpectedly contradicted the large body of epidemiological evidence relating to the potential benefits of dietary carotenoids. Not only did betaCT show no benefit, it was associated with significant increases in lung cancer incidence, cardiovascular diseases, and total mortality. These findings aroused widespread scientific debate that is still ongoing. It also raised the suspicion that betaCT may even possess co-carcinogenic properties. In this review, we summarize the current data on the co-carcinogenic properties of betaCT that is attributed to its role in the induction of carcinogen metabolizing enzymes and the over-generation of oxidative stress. The data presented provide convincing evidence of the harmful properties of this compound if given alone to smokers, or to individuals exposed to environmental carcinogens, as a micronutrient supplement. This has now been directly verified in a medium-term cancer transformation bioassay. In the context of public health policies, while the benefits of a diet rich in a variety of fruits and vegetables should continue to be emphasized, the data presented here point to the need for consideration of the possible detrimental effects of certain isolated dietary supplements, before mass cancer chemoprevention clinical trials are conducted on human subjects. This is especially important for genetically predisposed individuals who are environmentally or occupationally exposed to mutagens and carcinogens, such as those found in tobacco smoke and in industrial settings.     

Conversion of IQ, a dietary pyrolysis carcinogen to a direct-acting mutagen by normal intestinal bacteria of humans

The dietary carcinogen, 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ) is mutagenic in the Salmonella/microsomal mutagenicity assay when activated by microsomal enzymes. IQ is found in many cooked foods, notably fried beef and pork. In laboratory rodents IQ is carcinogenic. We showed that mixed and pure cultures of human intestinal anaerobes, notably Eubacterium spp., metabolized IQ to 2-amino-3,6-dihydro-3-methyl-7H-imidazo[4,5-f]quinoline-7-one (HOIQ). Unlike IQ, both the synthetic and bacterially produced HOIQ were direct-acting mutagens, i.e. active without microsomal activation. This new direct-acting mutagen, from the bacterial metabolism of a dietary pyrolysis carcinogen, raises new concerns about the possible role of this class of genotoxins in the etiology of human cancer.     

Multistep carcinogenesis: a chain reaction of aneuploidizations

Carcinogenesis is a multistep process in which new, parasitic and polymorphic cancer cells evolve from a single, normal diploid cell. This normal cell is converted to a prospective cancer cell, alias "initiated", either by a carcinogen or spontaneously. The initiated cell typically does not have a new distinctive phenotype yet, but evolves spontaneously--over months to decades--to a clinical cancer. The cells of a primary cancer also evolve spontaneously towards more and more malignant phenotypes. The outstanding genotype of initiated and cancer cells is aneuploidy, an abnormal balance of chromosomes, which increases and varies in proportion with malignancy. The driving force of the spontaneous evolution of initiated and cancerous cells to ever more abnormal phenotypes is said to be their "genetic instability". However, since neither the instability of cancer phenotypes nor the characteristically slow kinetics of carcinogenesis are compatible with gene mutation, we propose here that the driving force of carcinogenesis is the inherent instability of aneuploid karyotypes. Aneuploidy renders chromosome structure and segregation error-prone, because it unbalances mitosis proteins and the many teams of enzymes that synthesize and maintain chromosomes. Thus, carcinogenesis is initiated by a random aneuploidy, which is induced either by a carcinogen or spontaneously. The resulting karyotype instability sets off a chain reaction of aneuploidizations, which generate ever more abnormal and eventually cancer-specific combinations and rearrangements of chromosomes. According to this hypothesis the many abnormal phenotypes of cancer are generated by abnormal dosages of thousands of aneuploid, but un-mutated genes.     

Multistep Carcinogenesis: A Chain Reaction of Aneuploidizations

Carcinogenesis is a multistep process in which new, parasitic and polymorphic cancer cells evolve from a single, normal diploid cell. This normal cell is converted to a prospective cancer cell, alias "initiated", either by a carcinogen or spontaneously. The initiated cell typically does not have a new distinctive phenotype yet, but evolves spontaneously—over months to decades—to a clinical cancer. The cells of a primary cancer also evolve spontaneously towards more and more malignant phenotypes. The outstanding genotype of initiated and cancer cells is aneuploidy, an abnormal balance of chromosomes, which increases and varies in proportion with malignancy. The driving force of the spontaneous evolution of initiated and cancerous cells to ever more abnormal phenotypes is said to be their "genetic instability". However, since neither the instability of cancer phenotypes nor the characteristically slow kinetics of carcinogenesis are compatible with gene mutation, we propose here that the driving force of carcinogenesis is the inherent instability of aneuploid karyotypes. Aneuploidy renders chromosome structure and segregation error-prone, because it unbalances mitosis proteins and the many teams of enzymes that synthesize and maintain chromosomes. Thus, carcinogenesis is initiated by a random aneuploidy, which is induced either by a carcinogen or spontaneously. The resulting karyotype instability sets off a chain reaction of aneuploidizations, which generate ever more abnormal and eventually cancer-specific combinations and rearrangements of chromosomes. According to this hypothesis the many abnormal phenotypes of cancer are generated by abnormal dosages of thousands of aneuploid, but un-mutated genes.     

Chronic Exposure to Combined Carcinogens Enhances Breast Cell Carcinogenesis with Mesenchymal and Stem-Like Cell Properties

Breast cancer is the most common type of cancer affecting women in North America and Europe. More than 85% of breast cancers are sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce cellular carcinogenesis, we studied the activity of environmental carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), and dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) using our breast cell carcinogenesis model. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP in both non-cancerous and cancerous breast cells. Co-exposure was more potent than sequential exposure to combined NNK and B[a]P followed by PhIP in inducing carcinogenesis. Initiation of carcinogenesis was measured by transient endpoints induced in a single exposure, while progression of carcinogenesis was measured by acquisition of constitutive endpoints in cumulative exposures. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species elevation, and increased cellular proliferation. Constitutive endpoints included various cancer-associated properties and signaling modulators, as well as enrichment of cancer stem-like cell population and activation of the epithelial-to-mesenchymal transition program. Using transient and constitutive endpoints as targets, we detected that a combination of the green tea catechins ECG and EGCG, at non-cytotoxic levels, was more effective than individual agents in intervention of cellular carcinogenesis induced by combined NNK, B[a]P, and PhIP. Thus, use of combined ECG and EGCG should be seriously considered for early intervention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens.     

Mechanisms by which resistant starches and non-starch polysaccharide sources affect the metabolism and disposition of the food carcinogen, 2-amino-3-methylimidazo[4,5-f]quinoline

Although both non-starch polysaccharides (NSP) and resistant starches (RS) are included in current definitions of dietary fibre, our previous work has suggested fundamental differences in the way in which these two classes of material affect the disposition and absorption of a dietary carcinogen. The present studies explore whether different effects on carcinogen metabolism could play a role in the contrasting patterns seen previously. Groups of female Wistar rats were pre-fed for 4 weeks one of five types of defined diet (AIN-76). The control diet contained 35% maize starch and no dietary fibre. The RS-containing diets had all the maize starch substituted with either Hi-maize or potato starch. In the NSP-containing diets, 10% of the maize starch was substituted with dietary fibre in the form of either lignified plant cell walls (wheat straw) or soluble dietary fibre (apple pectin). Pre-fed rats were gavaged with the food carcinogen, [2-14C] 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and plasma and urinary metabolites characterized using HPLC at various time intervals after administration. After 4 h gavage, plasma from rats on both RS-containing diets contained significantly higher levels of intact IQ and lower levels of the major metabolites, IQ-5-O-glucuronide and IQ-5-sulfate, as compared with plasma from the negative control group at this time. In contrast, plasma from animals on the NSP-containing wheat straw diet (and to a lesser extent the apple pectin diet) showed significantly lower levels of intact IQ, and significantly higher levels of the two major metabolites, as compared with those from the control rats. These different metabolite profiles were also reflected in different urinary excretion profiles. Urine from rats pre-fed RS-containing diets revealed significantly slower metabolite excretion as compared with urine from rats that had been given the NSP-containing diets. Western blotting methodologies also profiled differences between the effects of these two types of dietary fibre in the expression of xenobiotic metabolizing enzymes. We conclude that changes in activity and expression of xenobiotic metabolising enzymes could play a role in the contrasting effects of these two types of dietary fibre on carcinogen uptake and disposition.     

Nutrient influences on toxicity and carcinogenicity

Essential nutrients and toxicants often coexist in the diet of humans and animals. Interactions among nutrients and chemicals in the diet may alter the toxicity of the chemical or the requirement for or availability of specific nutrients. Such interactions have been demonstrated among toxins and dietary protein, trace elements, and vitamins. Certain nutrients may also alter the response to certain drugs, and some drugs, such as oral contraceptives, may alter the availability of some nutrients. The carcinogenicity of some compounds and the subsequent promotion of tumor growth are affected by nutrients such as fat, vitamins, and lipotropes and by such minor dietary constituents as naturally occurring indoles and synthetic preservatives. In this paper we review such interactions as well as the mechanisms responsible for them.     

Diet and cancer prevention: Dietary compounds,dietary MicroRNAs,and dietary exosomes

Cancer is one of main health public problems worldwide. Several factors are involved in beginning and development of cancer. Genetic and internal/external environmental factors can be as important agents that effect on emerging and development of several cancers. Diet and nutrition may be as one of important factors in prevention or treatment of various cancers. A large number studies indicated that suitable dietary patterns may help to cancer prevention or could inhibit development of tumor in cancer patients. Moreover, a large numbers studies indicated that a variety of dietary compounds such as curcumin, green tea, folat, selenium, and soy isoflavones show a wide range anti‐cancer properties. It has been showed that these compounds via targeting a sequence of cellular and molecular pathways could be used as suitable options for cancer chemoprevention and cancer therapy. Recently, dietary microRNAs and exosomes have been emerged as attractive players in cancer prevention and cancer therapy. These molecules could change behavior of cancer cells via targeting various cellular and molecular pathways involved in cancer pathogenesis. Hence, the utilization of dietary compounds which are associated with powerful molecules such as microRNAs and exosomes and put them in dietary patterns could contribute to prevention or treatment of various cancers. Here, we summarized various studies that assessed effect of dietary patterns on cancer prevention shortly. Moreover, we highlighted the utilization of dietary compounds, dietary microRNAs, and dietary exosomes and their cellular and molecular pathways in cancer chemoprevention.     

Exposure level monitor of a carcinogenic glutamic acid pyrolysis product in rabbits

In order to determine a suitable indicator for estimating the exposure levels of the dietary carcinogen 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), a carcinogenic glutamic acid pyrolysis product, the levels of Glu-P-1 bound to blood components were monitored for 8 weeks by a high-performance liquid chromatography method after the dietary carcinogen was administered as single oral doses (0.2-50 mg) to rabbits. In all rabbits dosed with Glu-P-1, Glu-P-1 in erythrocytes was detectable even on day 42 after administration. Glu-P-1 in plasma disappeared faster than did Glu-P-1 in erythrocytes. Glu-P-1 levels in rabbit hemoglobin were linearly related to administered doses at all points of time investigated. The results suggest that Glu-P-1 covalently bound to hemoglobin is very suitable for monitoring long-term exposure levels.     

Prevention of cancer: restriction of nutritional energy intake (joules)

1. The reduction of nutritional energy intake (joules) often reduces the incidence of both spontaneous and induced cancers in humans and experimental animals in an approximately dose-dependent manner. 2. To achieve the best preventive effect, the reduction of dietary intake should begin well before the carcinogen insult, should be intense enough (lowering the intake of joules by at least approx. 25-30%) and should last a long time, preferably even life-long. 3. This preventive effect depends upon the strain, sex and age of animals, the kind of carcinogenic insult and also the susceptibility of the target tissue. 4. The mechanism by which the dietary restriction may exert its protective action may involve changes in the hormonal equilibria, influences upon the immuno-surveillance, changes of activities of enzymes involved in carcinogen metabolism and other factors. 5. Since over-eating and the resulting obesity constitutes a pronounced risk factor for the incidence of cancer and other diseases, lowering the nutritional energy intake represents today the simplest, cheapest and most effective way to prevent cancer in the general population.     

Metabolic routing of dietary nutrients in birds: effects of diet quality and macronutrient composition revealed using stable isotopes

During fall migration many songbirds switch from consuming primarily insects to consuming mostly fruit. Fruits with more carbohydrates and less protein may be sufficient to rebuild expended fat stores, but such fruits may be inadequate to replace catabolized protein. We manipulated the concentrations and isotopic signatures of macronutrients in diets fed to birds to study the effects of diet quality on metabolic routing of dietary nutrients. We estimated that approximately 45% and 75%, respectively, of the carbon in proteinaceous tissue of birds switched to high- or low-protein diets came from nonprotein dietary sources. In contrast, we estimated that approximately 100% and 20%-80%, respectively, of the nitrogen in proteinaceous tissues of birds switched to high- or low-protein diets was attributable to dietary protein. Thus, the routing and assimilation of dietary carbon and nitrogen differed depending on diet composition. As a result, delta (15)N of tissues collected from wild animals that consume high-quality diets may reliably indicate the dietary protein source, whereas delta (13)C of these same tissues is likely the product of metabolic routing of carbon from several macronutrients. These results have implications for how isotopic discrimination is best estimated and how we can study macronutrient routing in wild animals.