Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A case-control study of colorectal cancer, consisting of 157 cases and 380 controls matched by sex, ethnicity, decade of age and county of residence was performed to explore the associations between environmental exposure, metabolic polymorphisms and cancer risk. Participants were required to provide a blood sample, undergo caffeine phenotyping and complete an in-person interview that evaluated meat consumption, cooking methods and degree of doneness. A color atlas of foods cooked to different degrees of doneness was used to estimate food preparation techniques and food models were used to estimate serving portion sizes. Data was analyzed using a reference database of heterocyclic amine (HCA) exposure based on the food preferences chosen from the atlas. Data regarding individual food items cooked to different levels of doneness, as well as summary variables of foods and of food groups cooked to different degrees of doneness were also evaluated in a univariate analysis for association with colorectal cancer case status. Three measures of metabolic variation, hGSTA1 genotype, SULT1A1 genotype and the phenotype for CYP2A6 were also evaluated for possible association with colon cancer. While higher exposure to HCAs was strongly associated with colorectal cancer risk, increased consumption of five red meats cooked well done or very well done produced comparable odds ratios (OR) for colorectal cancer risk (OR=4.36, 95% CI 2.08-9.60) for the highest quartile of exposure. Similarly, individuals in the most rapid CYP2A6 phenotype quartile showed an odds ratio (OR = 4.18, 95% CI 2.03-8.90). The ORs for the low activity hGSTA1 and low activity SULT1A1 alleles were 2.0, 95% CI 1.0-3.7 and 0.6, 95% CI 0.3-1.1, respectively. Individual measures of specific HCAs provided little improvement in risk assessment over the measure of meat consumption, suggesting that exposure to other environmental or dietary carcinogens such as nitrosamines or undefined HCAs may contribute to colorectal cancer risk.
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PMID:Analysis of total meat intake and exposure to individual heterocyclic amines in a case-control study of colorectal cancer: contribution of metabolic variation to risk. 1235 Nov 57

Heterocyclic amines (HAAs) and polycyclic hydrocarbons are suspected colorectal cancer (CRC) carcinogens that are found in well-done meat. They require metabolic activation by phase I enzymes, such as the smoking-inducible CYP1A isoenzymes. N-acetyltransferase 2 (NAT2) also play a role in the further activation of HAAs. We conducted a population-based case-control study in Hawaii to test the associations of preference for well-done red meat and HAA intake with colon and rectal cancers, as well as the modifying effects of NAT2 and CYP1A2. We interviewed 727 Japanese, Caucasian or Native Hawaiian cases and 727 controls matched on sex, age, and ethnicity. HAA intake was estimated based on consumption of meat and fish for each of several cooking methods and doneness levels. A subgroup of 349 cases and 467 controls was phenotyped for CYP1A2 by a caffeine test. We found that preference for well-done red meat was associated with a 8.8-fold increased risk of CRC (95% CI: 1.7-44.9) among ever-smokers with the NAT2 and CYP1A2 rapid phenotypes, compared to ever-smokers with low NAT2 and CYP1A2 activities and who preferred their red meat rare or medium. A dose-dependent association was also found between the HAA intake estimates and male rectal cancer, with a two- to three-fold increase in risk from the low (T(1)) to high (T(3)) tertile of intake for each HAA. This association was strongest for MeIQx. HAA intake was not associated with male colon cancer or colon or rectal cancer in women. These data provide support to the hypothesis that exposure to pyrolysis products through consumption of well-done meat increases the risk of CRC, particularly in individuals who smoke and are genetically susceptible (as determined by a rapid phenotype for both NAT2 and CYP1A2). An attempt to examine the risk associated with specific HAAs suggested that the main HAAs increase risk of rectal cancer in men and that they do not appreciably affect risk of rectal cancer in women or of colon cancer in either sex.
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PMID:Well-done red meat, metabolic phenotypes and colorectal cancer in Hawaii. 1235 Nov 60

Research on cancer chemoprevention is an important approach for decreasing both the incidence and number of deaths from cancer. The use of tamoxifen to prevent breast cancer, finasteride to prevent prostate cancer, and aspirin to prevent colon cancer are recent examples of cancer chemoprevention. This article describes research from my laboratory and related research from other laboratories on the effects of enzyme induction on chemical carcinogenesis as an approach to cancer chemoprevention, as well as studies on the inhibitory effects of curcumin, caffeine, (-)-epigallocatechin gallate (EGCG), and tea in animal models of carcinogenesis. The later substances appear to work, at least in part, by enhancing apoptosis in DNA-damaged cells or in tumors. The results of our studies and those of others provide a rationale for clinical trials on the potential chemopreventive effects of curcumin, caffeine, EGCG, and tea on the formation of cancer of the skin, mouth, esophagus, stomach, and colon in people with precancerous lesions and a high risk of developing these cancers. It was pointed out that several compounds that are effective cancer chemopreventive agents in one experimental setting can enhance carcinogenesis in another experimental setting. These results suggest that it may be necessary to tailor the cancer chemopreventive regimen to individual subjects with known carcinogen exposures or to high cancer risk individuals with mechanistically understood pathways of carcinogenesis so that chemopreventive agents with known mechanisms of action can be better customized to the individual and selected on a more rational basis.
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PMID:Enzyme induction and dietary chemicals as approaches to cancer chemoprevention: the Seventh DeWitt S. Goodman Lecture. 1461 89

Epidemiologic evidence indicates an inverse association of folate intake with risk of colorectal cancer, but whether this association is modified by intake of caffeine (in coffee and tea) or cigarette smoking--factors that possibly interfere with folate--has not been studied. Thus, we examined whether the association between dietary folate intake and incidence of colorectal cancer is modified by caffeine intake and smoking. Cox proportional hazards modeling was used to estimate rate ratios relating dietary folate intake to colorectal cancer incidence among 61,433 women ages 40 to 75 years at recruitment into the Swedish Mammography Cohort in 1987 to 1990. From March 1987 through June 2004, a total of 805 incident cases of colorectal cancer were diagnosed. After controlling for age and other potential confounders, we observed an inverse association between dietary folate intake and risk of colon cancer (rate ratio for the highest versus the lowest quintile, 0.61; 95% confidence interval, 0.41-0.91; P(trend) = 0.02), but not of rectal cancer (rate ratio, 0.93; 95% confidence interval, 0.55-1.56; P(trend) = 0.97). The inverse association between dietary folate intake and colon cancer risk was most pronounced among smokers (P(interaction) = 0.03). We found no apparent modification of risk by caffeine intake. Findings from this population-based cohort study support an inverse association between dietary folate intake and risk of colon cancer and suggest that smokers might benefit most from a high dietary folate intake.
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PMID:A prospective study of dietary folate intake and risk of colorectal cancer: modification by caffeine intake and cigarette smoking. 1576 61

The present study was designed to investigate the effects of two main constituents of green tea, (-)-epigallocatechin-3-gallate (EGCG) and caffeine, on intestinal tumorigenesis in Apc(min/+) mice, a recognized mouse model for human intestinal cancer, and to elucidate possible mechanisms involved in the inhibitory action of the active constituent. We found that p.o. administration of EGCG at doses of 0.08% or 0.16% in drinking fluid significantly decreased small intestinal tumor formation by 37% or 47%, respectively, whereas caffeine at a dose of 0.044% in drinking fluid had no inhibitory activity against intestinal tumorigenesis. In another experiment, small intestinal tumorigenesis was inhibited in a dose-dependent manner by p.o. administration of EGCG in a dose range of 0.02% to 0.32%. P.o. administration of EGCG resulted in increased levels of E-cadherin and decreased levels of nuclear beta-catenin, c-Myc, phospho-Akt, and phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) in small intestinal tumors. Treatment of HT29 human colon cancer cells with EGCG (12.5 or 20 micromol/L at different times) also increased protein levels of E-cadherin by 27% to 58%, induced the translocation of beta-catenin from nucleus to cytoplasm and plasma membrane, and decreased c-Myc and cyclin D1 (20 micromol/L EGCG for 24 hours). These results indicate that EGCG effectively inhibited intestinal tumorigenesis in Apc(min/+) mice, possibly through the attenuation of the carcinogenic events, which include aberrant nuclear beta-catenin and activated Akt and ERK signaling.
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PMID:Inhibition of intestinal tumorigenesis in Apcmin/+ mice by (-)-epigallocatechin-3-gallate, the major catechin in green tea. 1628 56

5-Iododeoxyuridine (IUdR) and caffeine are recognized as potential radiosensitizers with different mechanisms of interaction with ionizing radiation (IR). To assess the interaction of these two types of radiosensitizers, we compared treatment responses to these drugs alone and in combination with IR in two p53-proficient and p53-deficient pairs of human colon cancer cell lines (HCT116 versus HCT116 p53-/- and RKO versus RKO E6). Based on clonogenic survival, the three single agents (IR, IUdR, and caffeine) as well as IUdR or caffeine combined with IR are less or equally effective in p53-deficient human tumor cells compared with p53-proficient tumor cells. However, using both radiosensitizers, a significantly greater radiosensitization was found in p53-deficient human tumor cells. To better understand the interaction of these two radiosensitizers, additional studies on DNA repair and cell cycle regulation were done. We found that caffeine enhanced IUdR-DNA incorporation and IUdR-mediated radiosensitization by partially inhibiting repair (removal) of IUdR in DNA. The repair of IR-induced DNA double-strand breaks was also inhibited by caffeine. However, these effects of caffeine on IUdR-mediated radiosensitization were not found in p53-proficient cells. Cell cycle analyses also showed a greater abrogation of IR-induced S- and G2-phase arrests by caffeine in p53-deficient cells, particularly when combined with IUdR. Collectively, these data provide the mechanistic bases for combining these two radiosensitizers to enhance tumor cytotoxicity. This differential dual mode of radiosensitization by combining IUdR and caffeine-like drugs (e.g., UCN-01) in p53-deficient human tumors may lead to a greater therapeutic gain.
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PMID:The interaction between two radiosensitizers: 5-iododeoxyuridine and caffeine. 1639 65

In the process of acquired drug resistance, the absence of tumour cell subpopulations already resistant before treatment implies an initial adaptive stage of cell growth following drug exposure that, under the selective pressure of the drug, allows the emergence of stably resistant cell variants. Here, we show that p53-defective HT-29 colon cancer cells overcome methotrexate-induced cell death owing to DNA damage checkpoint-mediated cell survival at the adaptive stage that precedes stable resistance acquisition. HT-29 cell cycle progression was dramatically delayed in the presence of a lethal dose of methotrexate, leading to DNA damage during S-phase transition and to cell death as treated cells progressed to G2 and M phases. As a result, the DNA damage checkpoint was induced as indicated by the presence of activated phosphorylated forms of checkpoint proteins Chk1 and Rad9. As we recently described, in-vitro resistance to methotrexate occurs without cell subpopulations already resistant before treatment, hence resistance is acquired through a multistep process that includes an early stage of transient cell survival. Our present results showed that this acute cell survival stage was due to a minor percentage of cells that could complete the first division cycle after drug exposure. Cell survival was enhanced by drug withdrawal during S-phase transition and suppressed if drug withdrawal was followed by treatment with the checkpoint-inhibitor drug caffeine. These results thus point to checkpoint-mediated transient adaptation as a target to prevent the emergence of acquired resistance to methotrexate.
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PMID:The DNA damage checkpoint is activated during residual tumour cell survival to methotrexate treatment as an initial step of acquired drug resistance. 1707 16

Inhibition of the nonsense-mediated decay (NMD) mechanism in cells results in stabilization of transcripts carrying premature translation termination codons. A strategy referred to as gene identification by NMD inhibition (GINI) has been proposed to identify genes carrying nonsense mutations. Genes containing frameshift mutations in colon cancer cell line have been identified using a modified version of GINI. To increase the efficiency of identifying mutant genes using GINI, we have now further improved the strategy. In this approach, inhibition of NMD with emetine is complemented with inhibiting NMD by blocking the phosphorylation of the hUpf1 protein with caffeine. In addition, to enhance the GINI strategy, comparing mRNA level alterations produced by inhibiting transcription alone or inhibiting transcription together with NMD following caffeine pretreatment were used for the efficient identification of false positives produced as a result of stress response to NMD inhibition. To demonstrate the improved efficiency of this approach, we analysed colon cancer cell lines showing microsatellite instability. Bi-allelic inactivating mutations were found in the FXR1, SEC31L1, NCOR1, BAT3, PHF14, ZNF294, C19ORF5 genes as well as genes coding for proteins with yet unknown functions.
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PMID:Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells. 1708 9

Frequent coffee consumption has been associated with a reduced risk of colorectal cancer in a number of case-control studies. Coffee is a leading source of methylxanthines, such as caffeine. The induction of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) is an essential feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is known to be a key regulator of this process. In this study, we investigated the effects of caffeine on HIF-1 protein accumulation and on VEGF and IL-8 expression in the human colon cancer cell line HT29 under hypoxic conditions. Our results show that caffeine significantly inhibits adenosine-induced HIF-1alpha protein accumulation in cancer cells. We show that HIF-1alpha and VEGF are increased through A3 adenosine receptor stimulation, whereas the effects on IL-8 are mediated via the A2B subtype. Pretreatment of cells with caffeine significantly reduces adenosine-induced VEGF promoter activity and VEGF and IL-8 expression. The mechanism of caffeine seems to involve the inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and Akt, leading to a marked decrease in adenosine-induced HIF-1alpha accumulation, VEGF transcriptional activation, and VEGF and IL-8 protein accumulation. From a functional perspective, we observe that caffeine also significantly inhibits the A3 receptor-stimulated cell migration of colon cancer cells. Conditioned media prepared from colon cells treated with an adenosine analog increased human umbilical vein endothelial cell migration. These data provide evidence that adenosine could modulate the migration of colon cancer cells by an HIF-1alpha/VEGF/IL-8-dependent mechanism and that caffeine has the potential to inhibit colon cancer cell growth.
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PMID:Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. 1748 4

Decitabine (DAC) and 5-azacitidine have recently been approved for the treatment of myelodysplastic syndrome. The pharmacodynamic effects of DAC and 5-azacitidine outside their known activity as inhibitors of DNA methyltransferases (DNMTs) require further investigation. The purpose of this study was to investigate the effect of DAC on the expression of p21(WAF1/CIP1), a gene with a putative CpG island surrounding its promoter region. Promoter methylation analysis of p21(WAF1/CIP1) in leukemia cells revealed the absence of CpG methylation. However, DAC upregulated p21(WAF1/CIP1) expression in a dose-dependent manner (ED(50)=103.34 nM) and induced G2/M cell cycle arrest in leukemia cells. Sequential application of DAC followed by different histone deacetylase inhibitors induced expression of p21(WAF1/CIP1) synergistically. Upregulation of p21(WAF1/CIP1) paralleled DAC-induced apoptosis (ED(50)=153 nM). Low doses of DAC induced gamma-H2AX expression (ED(50)=16.5 nM) and upregulated p21(WAF1/CIP1) in congenic HCT 116 colon cancer cells in a DNMT-independent and p53-dependent fashion. Inhibition of p53 transactivation by pifithrin-alpha or the kinase activity of ATM by either the specific ATM inhibitor KU-5593 or caffeine abrogated p21(WAF1/CIP1) upregulation, indicating that DAC upregulation of p21(WAF1/CIP1) was p53- and ATM-dependent in leukemia cells. In conclusion, DAC upregulates p21(WAF1/CIP1) in DNMT-independent manner via the DNA damage/ATM/p53 axis.
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PMID:p21(WAF1/CIP1) induction by 5-azacytosine nucleosides requires DNA damage. 1822 91


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