Dietary Carcinogens Research Articles

Renal cell carcinomas of chronic kidney disease patients harbor the mutational signature of carcinogenic aristolochic acid.

Aristolochic acid (AA) is a potent dietary cytotoxin and carcinogen, and an established etiological agent underlying severe human nephropathies and associated upper urinary tract urothelial cancers, collectively designated aristolochic acid nephropathy (AAN). Its genome-wide mutational signature, marked by predominant A:T > T:A transversions occurring in the 5'-CpApG-3' trinucleotide context and enriched on the nontranscribed gene strand, has been identified in human upper urinary tract urothelial carcinomas from East Asian patients and in experimental systems. Here we report a whole-exome sequencing screen performed on DNA from formalin-fixed, paraffin-embedded renal cell carcinomas (RCC) arising in chronic renal disease patients from a Balkan endemic nephropathy (EN) region. In the EN regions, the disease results from the consumption of bread made from wheat contaminated by seeds of Aristolochia clematitis, an AA-containing plant. In five of eight (62.5%) tested RCC tumor specimens, we observed the characteristic global mutational signature consistent with the mutagenic effects of AA. This signature was absent in the control RCC samples obtained from patients from a nonendemic, metropolitan region. By identifying a new tumor type associated with the AA-driven genome-wide mutagenic process in the context of renal disease, our results suggest new epidemiological and public health implications for the RCC incidence worldwide, particularly for the high-risk regions with unregulated use of AA-containing traditional herbal medicines.

Micronutrient, Genome Stabili ty and Degenerative Diseases: Nutrigenomics Concept of Disease Prevention - An Overview

Diet is a key factor in determining genomic stability is more important than previously imagined because it impacts on all relevant pathways like exposure to dietary carcinogens, DNA repair, DNA synthesis, epigenetic damage and apoptosis. Recent research focuses into how a single micronutrient deficiency is leading to genomic instability and development of degenerative diseases in various stages of life.The study aimed at finding the nutrigenomic mechanism of how a marginal deficiency of any single micronutrient is interrupting in DNA repairing, methylation and synthesis by taking nutrient-nutrient and nutrient-gene interaction into consideration. It also focuses on how recommended dietary allowance is important in achieving DNA integrity and genome stability to prevent degenerative diseases.Exhaustive review of research papers in genome health nutrigenomicsis involved in this study to explore, assimilate and analyze data to understand the importance of micronutrient in maintaining methylation of CpG sequence and preventing DNA oxidation or uracil misincorporation in DNA to stop disease occurrence in individuals.The study finds a direct link between micronutrient deficiency and increased epigenomic damage, resulting into elevated risk for adverse health outcomes during various stages of life like infertility, tumor development and cancer. The overview study concludes with a vision for a paradigm shift in disease prevention strategy based on diagnosis and micro-nutritional intervention of genome or epigenome damage on an individual basis, i.e. personalized prevention of degenerative diseases in genome health clinic.

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.

Interleukin-6 mediated upregulation of CYP1B1 and CYP2E1 in colorectal cancer involves DNA methylation, miR27b and STAT3.

Background:The pro-inflammatory cytokine interleukin-6 (IL6) promotes colorectal cancer (CRC) development. It is also known to regulate cytochrome P450 (CYP450) enzymes, which are involved in CRC tumour initiation and promotion via activation of chemical carcinogens. Here, IL6 regulation of CYP450 expression was investigated in CRC.Methods:The effect of IL6 on CYP 1A1, 1B1 and 2E1 expression was determined in vitro using CRC cell lines HCT116 and SW480, and CYP450 expression was determined by immunohistochemistry in CRC tissues previously shown to have increased levels of IL6.Results:In mechanistic studies, IL6 treatment significantly induced CYP1B1 and CYP2E1, but not CYP1A1, gene expression in HCT116 and SW480 cells. CYP2E1 expression regulation occurred via a transcriptional mechanism involving STAT3. For CYP1B1 regulation, IL6 downregulated the CYP1B1-targeting microRNA miR27b through a mechanism involving DNA methylation. In clinical samples, the expression of CYP1B1 and CYP2E1, but not CYP1A1, was significantly increased in malignant tissue overexpressing IL6 compared with matched adjacent normal tissue.Conclusions:Colonic inflammation with the presence of IL6 associated with neoplastic tissue can alter metabolic competency of epithelial cells by manipulating CYP2E1 and CYP1B1 expression through transcriptional and epigenetic mechanisms. This can lead to increased activation of dietary carcinogens and DNA damage, thus promoting colorectal carcinogenesis.

Abstract 1585: Chronic induction of breast cell carcinogenesis by multiple environmental and dietary carcinogens

Abstract Breast cancer, the most common type of cancer among North American and European women, is mostly sporadic and attributable to long-term exposure to small quantities of multiple carcinogens. To understand how multiple carcinogens act together to induce breast cell carcinogenesis, we investigated the activity of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the environmental carcinogen benzo[a]pyrene (B[a]P), and the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Non-cancerous human breast epithelial MCF10A cells were exposed to NNK, B[a]P, and PhIP sequentially or in combination and then analyzed for the acquisition of cancerous properties/endpoints. Transient endpoints included DNA damage, Ras-Erk-Nox pathway activation, reactive oxygen species (ROS) elevation, and increased cell proliferation. Constitutive endpoints included reduced dependence on growth factors, anchorage-independent growth, Ras-Erk-Nox pathway activation, and increased ROS and cell proliferation. To detect agents that can intervene with cellular carcinogenesis induced by NNK, B[a]P, and PhIP, we investigated the activity of green tea catechins effective in blocking these cancerous endpoints. Our study revealed, for the first time, that combined NNK and B[a]P enhanced breast cell carcinogenesis chronically induced by PhIP. Co-exposure was more potent than sequential exposure to induce initiation of cellular carcinogenesis measured by induction of transient endpoints in a single exposure and progression of carcinogenesis measured by cellular acquisition of constitutive endpoints in cumulative exposures. Our study also revealed that combined 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, co-exposure to NNK, B[a]P, and PhIP should be critically examined in epidemiological studies to reveal the impact of these carcinogens in the development of sporadic breast cancer. Use of combined ECG and EGCG should be seriously considered for chemoprevention of breast cell carcinogenesis associated with long-term exposure to environmental and dietary carcinogens. Citation Format: Lenora A. Pluchino, Hwa-Chain R. Wang. Chronic induction of breast cell carcinogenesis by multiple environmental and dietary carcinogens. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1585. doi:10.1158/1538-7445.AM2014-1585

Genetic analysis of colon tumors induced by a dietary carcinogen PhIP in CYP1A humanized mice: Identification of mutation of β-catenin/Ctnnb1 as the driver gene for the carcinogenesis.

Replacing mouse Cyp1a with human CYP1A enables the humanized CYP1A mice to mimic human metabolism of the dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), by N(2) -hydroxylation to a proximate carcinogen. Our previous study demonstrated that PhIP, combined with the dextrin sulfate sodium (DSS)-induced colitis, induces colon carcinogenesis in hCYP1A mice. Here, we employed whole exome sequencing and found multiple gene mutations in PhIP/DSS-induced colon tumors. Mutations in the exon 3 of Ctnnb1/β-catenin, however, were the predominant events. We further sequenced the key fragments of Apc, Ctnnb1, and Kras, because mutations of these genes in the humans are commonly found as the drivers of colorectal cancer. Mutations on either codon 32 or 34 in the exon 3 of Ctnnb1 were found in 39 out of 42 tumors, but no mutation was found in either Apc or Kras. The sequence context of codons 32 and 34 suggests that PhIP targets +3G in a TGGA motif of Ctnnb1. Since mutations that activate Wnt signal is a major driving force for human colorectal cancers, we conclude that the mutated β-catenin is the driver in PhIP/DSS-induced colon carcinogenesis. This result suggests that the colon tumors in hCYP1A mice mimic human colorectal carcinogenesis not only in the dietary etiology involving PhIP, but also in the aberrant activation of the Wnt signaling pathway as the driving force.

Pediatric Obesity Update

Welcome to the third Pediatric Obesity column for JPSN! This column’s missions are to provide information and resources to the pediatric surgical nurse caring for children affected by obesity and to share focused assessment and intervention strategies that can be incorporated into the practitioner’s daily practice. POOP, BUGS, AND OBESITY Beverly B. Haynes, MSN, RN, CPN The prevalence of obesity remains elevated, affecting at least 170 million children around the world. More than one third of children and one of every eight preschoolers in the United States are affected. Many theories are proposed, and much research is being conducted to find causes and treatments for pediatric obesity; still, there are no definite answers. Recently, there has been a surge in interest in stool microbiome as a possible culprit. The following is a brief introduction to this interesting and promising research. The microbiome is defined as the collective genomes of microbes (composed of bacteria, bacteriophages, fungi, protozoa, and viruses) that live in and on the human body (Yang, 2012). There are estimated to be about 100 million microbes per human body or about 10 times the number of human cells (Qin et al., 2010). Bacteria in the gut, especially in the lower gut, appear to influence digestion and energy extraction from food, catabolism of dietary toxins and carcinogens, synthesis of micronutrients, and fermentation of indigestible food substances and assist in the absorption of electrolytes and minerals (Payne et al., 2011). They also influence certain intestinal cell growth and play a role in the immune system. Differences in metabolic activities of gut bacteria may be responsible for the tendency of certain individuals to gain weight more easily or to experience diabetes, metabolic syndrome, and other diseases (Devaraj, Hemarajata, & Versalovic, 2013). There are two main phyla in the human gut, bacteroidetes (gram-negative rods) and firmicutes (gram-negative and gram-positive cocci). These phyla are known to be involved in energy harvest and are implicated in obesity. There are many subdivisions of these phyla found in the healthy human gut, creating a great diversity of microbes. Diversity is defined as the number and abundance distribution of distinct organism types. Low diversity in the gut is linked to obesity and bowel diseases (Human Microbiome Project Consortium, 2012). Studies of lean and obese mice and human twins suggest that individual differences in microbiomes influence metabolism leading to differences in resorption of energy from food substances, energy utilization, and energy storage. Obesity is noted to be more prevalent when the bacterial phyla are altered and diversity is decreased (Bervoets et al., 2013; Turnbaugh et al., 2009). The human intestine contains most bacteria (as opposed to other areas of the body) and is necessary for life because of bacterial influence on physiology and nutrient harvest. As part of the Human Microbiome Project, bacteria in the body are cataloged, and the impact these bacteria have on humans is studied (Qin et al., 2010). Various methods of identifying the microbiome are used, but the most useful involve DNA testing and metagenomics. In the past, bacteria were identified using culture techniques. This only allowed differentiation between gram-positive and gram-negative bacteria. Many more bacteria remained unidentified; by using DNA methods, scientists are able to identify many more bacteria. In addition, researchers are able to determine how the bacteria function, allowing them to study bacterial influences on the body. Knowing the bacterial influence of bacteria within the body has given clinicians the ability to change the course of disease. For example, by studying Clostridium difficile, researchers were able to develop a treatment for Clostridium difficile infections unresponsive to antibiotic therapy. In these cases, a stool transplant using purified stool from a healthy donor is introduced via colonoscopy into several points in the colon. Recipients resumed healthy bowel patterns within 2–3 days of the transplant with no recurrence during the subsequent 6 months (Petrof et al., 2013). In summary, humans are host to vast bacterial populations that regulate our health. Changes in bacterial populations appear to have significant influence on the body, including obesity. Research continues to identify bacteria in the body and various influences that change bacterial populations or their function. In the area of obesity, there is hope that knowledge gained from these studies will allow new practices with regard to feeding routines at various ages for children worldwide resulting in the control of obesity. Understanding how bacteria function in other diseases and the treatment derived from that research may allow routine use of similar treatments, such as fecal transplantation, of obesity.

Effect of Thermal Treatments on the Formation of Heterocyclic Aromatic Amines in Various Meats

Heterocyclic aromatic amines (HAAs), the potential mutagens/carcinogens, are formed during cooking meat at higher temperature. The current study was designed to evaluate the effects of various cooking methods, i.e., pan frying, deep frying, charcoal grilling and roasting, on the formation of HAAs in three different types of meat, i.e., beef, chicken and mutton. Physicochemical analysis of thermally treated meat was carried out. Mineral profile such as Na, K, Fe, Cu, Zn and Mg was also determined. Two mutagenic HAAs, i.e., 1-methyl-9H-pyrido [4,3-b]indole (Harman) and 9H-pyrido-[4,3-b]indole (Norharman), were formed during cooking and extracted by solid phase extraction technique and analyzed by high-performance liquid chromatography using internal standards. The results showed that the amounts of Harman were higher than Norharman. Generally, the type and content of HAAs in cooked meat varies with cooking methods and conditions. Practical Applications Diet is one of the major factors that influence the tumor formation in humans. Epidemiologic and experimental evidence indicates that proteinaceous foods, especially meat cooked at higher temperatures, may lead to the formation of heterocyclic aromatic amines (HAAs). HAAs are the potential mutagens and contribute toward the carcinogenicity depending on many factors, including type of meat and cooking method. They vary in their chemical nature, mechanism of formation, amounts in different types of meat and meat products. They also show a variable range of metabolic behavior and carcinogenic potential. The exact identification of major risk factors, especially dietary carcinogens, could play a vital role in reducing cancer incidence and mortality. The present study was designed to investigate the influence of different cooking methods (pan frying, deep frying, charcoal grilling and roasting) on the formation of HAAs in various meats (chicken, beef and mutton). It is also evident from the results that the content of HAAs in cooked meat varied with cooking methods and cooking conditions, and data from this study could be used to assess the human intake of HAAs and also to identify conditions that minimize the formation and intake of HAAs.

Molecular and cellular cues of diet‐associated oral carcinogenesis—with an emphasis on areca‐nut‐induced oral cancer development

In modern times, potent dietary carcinogens are key contributors for neoplastic development. For oral squamous cell carcinoma (OSCC), one of the leading cancer types in developing countries, main oncogenic inducers/enhancers, including areca nut chewing, tobacco smoking, and alcohol consumption, were shown to promote cancer initiation/progression. Over decades, studies from different laboratories have identified underlying cellular and molecular mechanisms for carcinogen-induced OSCC. In this review, we will give an overview of where we are in understanding potential oral carcinogenic factors stimulated OSCC tumorigenesis, especially those associated with areca nut chewing in Asians, aiming to provide future scope of possible interception.

Prostate cancer: from the pathophysiologic implications of some genetic risk factors to translation in personalized cancer treatments

Several pathologies affect human prostate, such as prostate cancer (PC), which is the most common non-skin malignant cancer in Western male populations. A complex interaction between genetic and environmental factors (i.e. infectious agents, dietary carcinogens) and hormonal imbalances has been reported to have a fundamental role in PC pathophysiology by evoking chronic inflammation. Thus, chronic inflammation drives prostate carcinogenesis and neoplastic progression. No adequate biomarkers exist until now to guide PC prognosis and treatment. Accordingly, the research has particularly focused its attention on genetic variants in genes, codifying molecules of signaling innate immune/inflammatory and steroid metabolism pathways, which are able to modify the PC genetic susceptibility and clinical disease outcome. Single-nucleotide polymorphisms (SNPs) may operate in combination to create a 'risk profile'. Combinations of several inflammatory and sex steroid hormone pathway SNPs are found in PC patients. Thus, their combinations might be used as promising biomarkers in a pre- and post-treatment clinical PC setting. Indeed, their identification may hold promise for the realization of a personalized PC medicine. Many of these aspects are summarized in this report through the elucidation of literature data and the results of our studies.

Low dose effects of the dietary carcinogen acrylamide

Low dose effects of the dietary carcinogen acrylamide

AKT is critically involved in cooperation between obesity and the dietary carcinogen amino-1-methyl-6-phenylimidazo [4,5-b] (PhIP) toward colon carcinogenesis in rats

Obesity is highly associated with colon cancer development. Whereas it is generally attributed to pro-tumorigenic effects of high fat diet (HFD), we here show that a common genetic basis for predisposition to obesity and colon cancer might also underlie the close association. Comparison across multiple rat strains revealed that strains prone to colon tumorigenesis initiated by a dietary carcinogen amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) tended to develop obesity. Through transcriptome and extensive immunoblotting analyses, we identified the basal level of activated AKT in colonic crypts as a biomarker for the common predisposition. Notably, PhIP induced activation of AKT, which could persist for several weeks under a low fat diet (LFD), but not under HFD. On the other hand, PhIP and HFD independently induced Wnt pathway activation and inhibited apoptosis, through distinct mechanisms involving GSK-3β, caspase 3 and poly-ADP ribose polymerase (PARP). Taken together, these observations provide mechanistic insights into how PhIP-induced activation of AKT might cooperate with HFD at multiple levels toward development of colon cancer.

S11 * ALCOHOL AS A MODULATOR OF LIVER DISEASE PROGRESSION ESBRA & EASL JOINT SYMPOSIUM

S11 * ALCOHOL AS A MODULATOR OF LIVER DISEASE PROGRESSION ESBRA & EASL JOINT SYMPOSIUM

Mo1957 Histopathological and Immune Studies of Angiogenesis and Gastric Cancer Induced by H. pylori Infection and a Dietary Carcinogen in Macaques

Mo1957 Histopathological and Immune Studies of Angiogenesis and Gastric Cancer Induced by H. pylori Infection and a Dietary Carcinogen in Macaques

Mo1953 Genetic Diversity of a Single H. pylori Strain Over a Five-Year Period in a Primate Model: Effect of Long Term Colonization and of a Dietary Carcinogen

Mo1953 Genetic Diversity of a Single H. pylori Strain Over a Five-Year Period in a Primate Model: Effect of Long Term Colonization and of a Dietary Carcinogen

Abstract 2193: Characterization of the aggresome targeted Q141K ABCG2/BCRP variant.

Abstract ABCG2 is a member of the G subfamily of human ABC transporters. It is an ATP-dependent protein and is a half-transporter that must dimerize for function. In various tumor cell lines, ABCG2 was involved in resistance to chemotherapy, by transporting numerous anticancer agents including tyrosine kinase inhibitors. Studies show the transporter has an important role in normal tissue protection, including the blood-brain and maternal-fetal barriers. It has also been observed that ABCG2 may play a protective role with respect to exposure to smoke or dietary carcinogens. A common variant in human ABCG2, the polymorphism Q141K, impairs expression and function, thereby reducing drug clearance and increasing the toxicity of chemotherapy and other substrate drugs. Although the activity of the Q141K variant is regularly described, biochemical data remain rare. Q141K has an impaired trafficking to cell surface compared to the WT protein and is sequestered in the aggresome. Here we characterized the Q141K and WT protein in human cells, studying post-translational modification, biochemistry, dimerization status, half-life, and endocytosis. Glycosylation and phosphorylation are equivalent, as is ATP binding and hydrolysis, and substrate binding using IAAP competition assays. Cell treatment with romidepsin, an HDAC inhibitor approved by FDA as an anticancer agent, restored the impaired variant trafficking, leading to an increase in drug efflux. The restoration of ABCG2 Q141K function has potential applications in oncology and in medicine, in improving normal tissue protection and drug elimination, as well as in cancer prevention since several carcinogens are substrates for ABCG2. Citation Format: Agnes Basseville, Suneet Shukla, Akina Tamaki, Robert Robey, Suresh V. Ambudkar, Susan E. Bates. Characterization of the aggresome targeted Q141K ABCG2/BCRP variant. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2193. doi:10.1158/1538-7445.AM2013-2193

Abstract 202: Tocopherols inhibit the dietary carcinogen PhIP-induced prostate carcinogenesis in a CYP1A-humanized mouse model.

Abstract γ-TmT, a tocopherol mixture that is rich in γ-tocopherol (γ-T), containing 56.8% γ-T, 24.3% δ-T, 13.0% α-T and 1.5% β-T, has been shown to inhibit colon, lung, mammary and prostate tumorigenesis in our previous studies, whereas α-T was ineffective. The present work investigated the inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced prostate carcinogenesis in CYP1A-humanized (hCYP1A) mice by γ-TmT. Male hCYP1A mice, maintained on the AIN93M diet or the same diet supplemented with 0.3% γ-TmT, were treated with a dose of PhIP (200 mg/kg, i.g.). At week 40 after PhIP treatment, all mice developed high-grade prostate intraepithelial neoplasia (hgPIN) in the dorso-lateral glands. The hgPIN was associated with elevated levels of 8-oxo-deoxyguanosine (8-oxo-dG), DNMT1, COX-2 and p-AKT, as well as with loss of expression of the tumor suppressor PTEN, E-cadherin, GSTP1 and Nrf2 in the dorso-lateral glands. In the γ-TmT group, the number of glands with hgPIN (per 100 glands) was significantly lower than the control group (14.6 ± 4.87 vs. 34.81 ± 3.87, p < 0.01). The γ-TmT treatment also prevented the elevation of 8-oxo-dG, COX-2 and p-AKT and the loss of PTEN and Nrf2. The γ-TmT treatment significantly increased the plasma levels of γ-T and δ-T (to 1.7 and 0.8 μM, respectively) as well as their side-chain degradation metabolites, carboxyethyl hydroxychromans and carboxymethylbutyl hydroxychromans (to 2.6-4.0 μM, higher than their parent tocopherols). In a short-term experiment, PhIP-treatment elevated levels of 8-oxo-dG, γH2AX and DNMT1, and caused gene expression changes in several p53-associated genes, including p53bp1, p21WAF1/CIP1, cyclin D1, Bax, Igf1 and cyclinG1 at 1 and/or 3 days after PhIP treatment. Dietary γ-TmT treatment partially prevented the elevation of 8-oxo-dG, γH2AX and DNMT1. This action may contribute to the prostate cancer preventive effect of tocopherols. The presently observed inhibitory activities of γ-TmT against prostate carcinogenesis are hypothesized to be due to the decrease of oxidative stress and inhibition of AKT phosphorylation by γ- and δ-tocopherols, and this hypothesis remains to be tested further (supported by NIH grants CA159361 & CA133021). Citation Format: Guangxun Li, Hong Wang, Anna B. Liu, Jayson X. Chen, Mao-Jung Lee, Chung S. Yang. Tocopherols inhibit the dietary carcinogen PhIP-induced prostate carcinogenesis in a CYP1A-humanized mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 202. doi:10.1158/1538-7445.AM2013-202

Identifying Molecular Targets of Lifestyle Modifications in Colon Cancer Prevention

One in four deaths in the United States is cancer-related, and colorectal cancer (CRC) is the second leading cause of cancer-associated deaths. Screening strategies are utilized but have not reduced disease incidence or mortality. In this regard, there is an interest in cancer preventive strategies focusing on lifestyle intervention, where specific etiologic factors involved in cancer initiation, promotion, and progression could be targeted. For example, exposure to dietary carcinogens, such as nitrosamines and polycyclic aromatic hydrocarbons influences colon carcinogenesis. Furthermore, dietary deficiencies could alter sensitivity to genetic damage and influence carcinogen metabolism contributing to CRC. High alcohol consumption increases the risk of mutations including the fact that acetaldehyde, an ethanol metabolite, is classified as a group 1 carcinogen. Tobacco smoke exposure is also a risk factor for cancer development; approximately 20% of CRCs are associated with smoking. Additionally, obese patients have a higher risk of cancer development, which is further supported by the fact that physical activity decreases CRC risk by 55%. Similarly, chronic inflammatory conditions also increase the risk of CRC development. Moreover, the circadian clock alters digestion and regulates other biochemical, physiological, and behavioral processes that could influence CRC. Taken together, colon carcinogenesis involves a number of etiological factors, and therefore, to create effective preventive strategies, molecular targets need to be identified and beleaguered prior to disease progression. With this in mind, the following is a comprehensive review identifying downstream target proteins of the above lifestyle risk factors, which are modulated during colon carcinogenesis and could be targeted for CRC prevention by novel agents including phytochemicals.

Capturing Labile Sulfenamide and Sulfinamide Serum Albumin Adducts of Carcinogenic Arylamines by Chemical Oxidation

Aromatic amines and heterocyclic aromatic amines (HAAs) are a class of structurally related carcinogens that are formed during the combustion of tobacco or during the high temperature cooking of meats. These procarcinogens undergo metabolic activation by N-oxidation of the exocyclic amine group to produce N-hydroxylated metabolites, which are critical intermediates implicated in toxicity and DNA damage. The arylhydroxylamines and their oxidized arylnitroso derivatives can also react with cysteine (Cys) residues of glutathione or proteins to form, respectively, sulfenamide and sulfinamide adducts. However, sulfur-nitrogen linked adducted proteins are often difficult to detect because they are unstable and undergo hydrolysis during proteolytic digestion. Synthetic N-oxidized intermediates of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogenic HAA produced in cooked meats, and 4-aminobiphenyl, a carcinogenic aromatic amine present in tobacco smoke, were reacted with human serum albumin (SA) and formed labile sulfenamide or sulfinamide adducts at the Cys(34) residue. Oxidation of the carcinogen-modified SA with m-chloroperoxybenzoic acid (m-CPBA) produced the arylsulfonamide adducts, which were stable to heat and the chemical reduction conditions employed to denature SA. The sulfonamide adducts of PhIP and 4-ABP were identified, by liquid chromatography/mass spectrometry, in proteolytic digests of denatured SA. Thus, selective oxidation of arylamine-modified SA produces stable arylsulfonamide-SA adducts, which may serve as biomarkers of these tobacco and dietary carcinogens.

The role of inflammatory mediators in the development of prostatic hyperplasia and prostate cancer

Benign prostatic hyperplasia and prostate cancer remain the most prevalent urologic health concerns affecting elderly men in their lifetime. Only 20% of benign prostatic hyperplasia and prostate cancer cases coexist in the same zone of the prostate and require a long time for initiation and progression. While the pathogenesis of both diseases is not fully understood, benign prostatic hyperplasia and prostate cancer are thought to have a multifactorial etiology, their incidence and prevalence are indeed affected by age and hormones, and they are associated with chronic prostatic inflammation. At least 20% of all human malignancies arise in a tissue microenvironment dominated by chronic or recurrent inflammation. In prostate malignancy, chronic inflammation is an extremely common histopathologic finding; its origin remains a subject of debate and may in fact be multifactorial. Emerging insights suggest that prostate epithelium damage potentially inflicted by multiple environmental factors such as infectious agents, dietary carcinogens, and hormones triggers procarcinogenic inflammatory processes and promotes cell transformation and disease development. Also, the coincidence of chronic inflammation and tumorigenesis in the peripheral zone has recently been linked by studies identifying so-called proliferative inflammatory atrophy as a possible precursor of prostatic intraepithelial neoplasia and prostate cancer. This paper will discuss the available evidence suggesting that chronic inflammation may be involved in the development and progression of chronic prostatic disease, although a direct causal role for chronic inflammation or infection in prostatic carcinogenesis has yet to be established in humans. Further basic and clinical research in the area, trying to understand the etiology of prostatic inflammation and its signaling pathway may help to identify new therapeutic targets and novel preventive strategies for reducing the risk of developing benign and malignant tumors of the prostate.