Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indole-3-carbinol (I3C), a naturally occurring compound of Brassica vegetables, has promising anticancer properties and activates an anti-proliferative pathway that induces a G1 cell cycle arrest of human breast cancer cells. A microarray analysis of I3C treated versus untreated MCF-7 breast cancer cells revealed that I3C increased expression of the interferon gamma receptor 1 (IFNgammaR1). Western blot and RT-PCR analysis demonstrated that I3C strongly and rapidly stimulated IFNgammaR1 gene expression. Transfection of a series of 5' deletion constructs of the IFNgammaR1 reporter plasmids revealed that I3C significantly stimulates the promoter activity of the IFNgammaR1 and uncovered an I3C-responsive region between -540 and -240 bp of the IFNgammaR1 promoter. I3C stimulation of the IFNgammaR1 expression suggests that indole treatment should enhance IFNgamma responsiveness in breast cancer cells. A combination of I3C and IFNgamma synergistically activated STAT1 proteins by increasing phosphorylation at the Tyr-701 site. In addition, I3C and IFNgamma together more effectively induced a G1 cell cycle arrest and stimulated expression of the p21(Waf1/Cip1) cell cycle inhibitor, compared with the effects of either agent alone. Our results suggest that one mechanism by which I3C mediates these anticancer effects is by stimulating expression of the IFNgammaR1 and augmenting the IFNgamma response in MCF-7 human breast cancer cells.
Carcinogenesis 2004 Jul
PMID:Indole-3-carbinol stimulates transcription of the interferon gamma receptor 1 gene and augments interferon responsiveness in human breast cancer cells. 1498 19

Indole-3-carbinol (I3C) is present in many cruciferous vegetables and is known to possess protective properties against chemically induced toxicity and carcinogenesis. In the present study, the antimutagenic potential of I3C has been evaluated using in vivo chromosomal aberration (CA) assay as a cytogenetic end point. Chromosomal analysis was carried out in mouse bone marrow cells following administration of 13C (5 mg/kg; i.p.) for 5 consecutive days. Cyclophosphamide (CP), a well known mutagen, was given at two dose levels of 25 mg/kg b.wt. and 100 mg/kg b.wt., respectively, 24 hours prior to the last dose of I3C. Two groups of five mice each were also injected with CP (25 or 100 mg/kg b.wt.) alone whereas for the vehicle control a group of mice was injected with normal saline only. The results revealed a significant inhibition in the frequencies of CP-induced CAs and aberrant cells in bone marrow cells of I3C-supplemented Swiss albino mice. The antimutagenic potential of 13C towards CP was also evident as the status of mitotic index (MI) was found to show an increment. This study revealed the antigenotoxic potential of I3C against CP-induced chromosomal mutations.
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PMID:Protective effects of indole-3-carbinol on cyclophosphamide-induced clastogenecity in mouse bone marrow cells. 1522 2

Indole-3-carbinol (I3C), found in cruciferous vegetables, has been shown to suppress or promote carcinogenesis depending on various animal models. Regarding its preventive effects, I3C acts as an anti-estrogen and can induce apoptosis, but precise mechanisms remain to be determined. Since I3C induces cytochrome P450 enzymes in the liver, it affects hydroxylation of estrogens and might therefore be expected to influence endometrial adenocarcinoma development. The present study was performed to clarify the effects of I3C using a rat two-stage endometrial carcinogenesis model, focusing on induction of cytochrome P450s and other estrogen-metabolic enzymes in the liver. First, to determine the estrogenic or anti-estrogenic activity, an uterotropic assay was conducted using ovariectomized Donryu rats (experiment 1). Second, to elucidate the effects on endometrial carcinogenicity, female Donryu rats initiated with a single dose of N-ethyl-N'-nitro-N-nitrosoguanidine into a uterine horn were fed 0 or 500 p.p.m. I3C in diets for 12 months (experiment 2). In experiment 3, similarly initiated animals received 0 or 2000 p.p.m. I3C in their diet, or 1 microg/kg 17beta-estradiol (E2) or 5 microg/kg 4-hydroxyestradiol (4HE) subcutaneously twice a week for 12 months. In the uterotrophic assay, neither 500 nor 2000 p.p.m. of I3C showed any estrogenic or anti-estrogenic activity. In the two uterine carcinogenicity studies, I3C and 4HE increased incidences of uterine adenocarcinomas and/or multiplicities of uterine proliferative lesions, E2-treatment being associated with a tendency for promotion. In the liver, I3C treatment consistently elevated estradiol 2- and 4-hydroxylase activities, in particular the latter, but without effects on estradiol 16alpha-hydoxylase activity. mRNAs for CYP 1A1, 1A2 and 1B1 were increased by I3C treatment, with translation confirmed immunohistochemically. These results suggest that induction of the CYP 1 family in the liver and sequential modulation of estrogen metabolism to increase 4HE might play a crucial role in promoting the effects of dietary I3C on endometrial adenocarcinoma development.
Carcinogenesis 2004 Nov
PMID:Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats initiated with N-ethyl-N'-nitro-N-nitrosoguanidine, with induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism. 1524 May 8

Studies have linked the consumption of broccoli and other cruciferous vegetables to a reduced risk of breast cancer. The phytochemical indole-3-carbinol (I3C), present in cruciferous vegetables, and its major acid-catalyzed reaction product 3,3'-diindolylmethane (DIM) have bioactivities relevant to the inhibition of carcinogenesis. In this study, the effect of DIM on angiogenesis and tumorigenesis in a rodent model was investigated. We found that DIM produced a concentration-dependent decrease in proliferation, migration, invasion and capillary tube formation of cultured human umbilical vein endothelial cells (HUVECs). Consistent with its antiproliferative effect, which was significant at only 5 microM DIM, this indole caused a G1 cell cycle arrest in actively proliferating HUVECs. Furthermore, DIM downregulated the expression of cyclin-dependent kinases 2 and 6 (CDK2, CDK6), and upregulated the expression of CDK inhibitor, p27(Kip1), in HUVECs. We observed further in a complementary in vivo Matrigel plug angiogenesis assay that, compared with vehicle control, neovascularization was inhibited up to 76% following the administration of 5 mg/kg DIM to female C57BL/6 mice. Finally, this dose of DIM also inhibited the growth of human MCF-7 cell tumor xenografts by up to 64% in female athymic (nu/nu) mice, compared with the vehicle control. This is the first study to show that DIM can strongly inhibit the development of human breast tumor in a xenograft model and to provide evidence for the antiangiogenic properties of this dietary indole.
Carcinogenesis 2005 Apr
PMID:3,3'-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice. 1566 11

Indole-3-carbinol (I3C), a naturally occurring compound found in vegetables of the Brassica genus, such as broccoli and cabbage, is a promising anticancer agent previously shown to induce a G(1) cell-cycle arrest in the cells of human lymph node carcinoma of prostate (LNCaP) through regulation of specific G(1)-acting cell-cycle components. Since the androgen receptor (AR) mediates proliferation and differentiation in the prostate and is expressed in nearly all human prostate cancers, the effects of I3C on AR expression and function were examined in LNCaP cells. Immunoblot and quantitative RT-PCR assays revealed that I3C inhibited the expression of AR protein and mRNA levels within 12 h of indole treatment. I3C downregulated the reporter activity of LNCaP cells transiently transfected with an AR promoter-luciferase plasmid, demonstrating that a unique response to I3C is the inhibition of AR promoter activity. In contrast to I3C, the natural I3C dimerization product 3,3'-diindolylmethane, which acts as an androgen antagonist, had no effect on AR expression. To determine the functional significance of the I3C-inhibited expression of AR, the AR-regulated prostate specific antigen (PSA) was utilized as a downstream indicator. I3C downregulated the expression of PSA transcripts and protein levels and inhibited PSA promoter activity, as well as that of a minimal androgen responsive element containing reporter plasmid. Expression of exogenous AR prevented the I3C disruption of androgen-induced PSA expression. Taken together, our results demonstrate that I3C represses AR expression and responsiveness in LNCaP cells as a part of its antiproliferative mechanism.
Carcinogenesis 2005 Nov
PMID:Indole-3-carbinol inhibition of androgen receptor expression and downregulation of androgen responsiveness in human prostate cancer cells. 1595 18

Catalase is a highly conserved heme-containing antioxidant enzyme known for its ability to degrade hydrogen peroxide into water and oxygen. In low concentrations of hydrogen peroxide, the enzyme also exhibits peroxidase activity. We report that mammalian catalase also possesses oxidase activity. This activity, which is detected in purified catalases, cell lysates, and intact cells, requires oxygen and utilizes electron donor substrates in the absence of hydrogen peroxide or any added cofactors. Using purified bovine catalase and 10-acetyl-3,7-dihydroxyphenoxazine as the substrate, the oxidase activity was found to be temperature-dependent and displays a pH optimum of 7-9. The Km for the substrate is 2.4 x 10(-4) m, and Vmax is 4.7 x 10(-5) m/s. Endogenous substrates, including the tryptophan precursor indole, the neurotransmitter precursor beta-phenylethylamine, and a variety of peroxidase and laccase substrates, as well as carcinogenic benzidines, were found to be oxidized by catalase or to inhibit this activity. Several dietary plant micronutrients that inhibit carcinogenesis, including indole-3-carbinol, indole-3-carboxaldehyde, ferulic acid, vanillic acid, and epigallocatechin-3-gallate, were effective inhibitors of the activity of catalase oxidase. Difference spectroscopy revealed that catalase oxidase/substrate interactions involve the heme-iron; the resulting spectra show time-dependent decreases in the ferric heme of the enzyme with corresponding increases in the formation of an oxyferryl intermediate, potentially reflecting a compound II-like intermediate. These data suggest a mechanism of oxidase activity involving the formation of an oxygen-bound, substrate-facilitated reductive intermediate. Our results describe a novel function for catalase potentially important in metabolism of endogenous substrates and in the action of carcinogens and chemopreventative agents.
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PMID:Characterization of the oxidase activity in mammalian catalase. 1607 30

Indole-3-carbinol (I3C) and phenethyl isothiocyanate (PEITC) are breakdown products of the glucosinolates glucobrassicin and gluconasturtiin, respectively, and are thought to reduce carcinogen activation by P450 enzymes. To assess the effects of these compounds on colon cancer risk, rats were divided into five groups and fed the following diets: control diet (AIN-93G), or diets with PEITC or I3C added to the control diet: high-PEITC (3.37 mmols/kg diet-high level of PEITC), low-PEITC (0.67 mmols/kg-low level of PEITC), high-I3C (6.8 mmols/kg-high level of I3C) and low-I3C (1.36 mmols/kg-low level of I3C). Diets were fed for 2 weeks before and 10 weeks after administration of the colon carcinogen azoxymethane. Precancerous lesion (aberrant crypt foci, ACF) number in the distal colon was significantly lower in both high-I3C and low-I3C groups (6.9 +/- 0.8 and 5.9 +/- 0.59 per cm2, respectively) when compared with the control group (10.4 +/- 0.9). No significant difference in ACF number was found between the PEITC group and the control group. ACF expressing sialomucin, thought to indicate ACF more likely to progress to tumors, were greater in the high-PEITC group (13 +/- 3) than the control (5.6 +/- 2). Mucin-depleted ACF, suggested to have the greatest tumorigenic potential, tended to be lower in the low-I3C group (P < 0.06) compared with the control group. Mucosal apoptotic and cell proliferation labeling indices did not differ among groups, suggesting that reduction in the ACF number by I3C does not involve alterations in mucosal cell kinetics. No significant differences were found among the groups in hepatic cytochrome P450 2E1 (CYP2E1) activity, the first enzyme involved in activation of azoxymethane. However, there was increased activity of NADPH- and NADH reductases with high-I3C, which are the enzymes involved in the transfer of reducing equivalents to cytochrome P450. These results suggest that I3C lowers colon cancer risk through a mechanism not involving reduction of carcinogen activation by CYP2E1.
Carcinogenesis 2006 Feb
PMID:Effects of indole-3-carbinol and phenethyl isothiocyanate on colon carcinogenesis induced by azoxymethane in rats. 1611 56

A review of almost 2000 studies showed that the large majority of 39 putative cancer chemopreventive agents induced "spontaneous" apoptosis. Inhibition of the programmed cell death triggered by a variety of stimuli was consistently reported only with ascorbic acid, alpha-tocopherol, and N-acetylcysteine (NAC). We performed experimental studies in rodents exposed to cigarette smoke, either mainstream (MCS) or environmental (ECS), and UV-A/B-containing light. The nonsteroidal anti-inflammatory drug sulindac did not affect the apoptotic process in the skin of light-exposed mice and in the lungs of ECS-exposed mice. Likewise, 5,6-benzoflavone, indole-3-carbinol, 1,2-dithiole-3-thione and oltipraz failed to modulate apoptosis in the respiratory tract of ECS-exposed rats. Phenethyl isothiocyanate further enhanced the frequency of apoptosis in pulmonary alveolar macrophages and bronchial epithelial cells, and upregulated several genes in the lung of ECS-exposed rats. Both individually and in combination with oltipraz, NAC inhibited apoptosis in the respiratory tract of rats exposed either to MCS or ECS. Moreover, NAC attenuated the ECS-related overexpression of proapoptotic genes and normalized the levels of proapoptotic proteins in rat lung. The transplacental administration of NAC to mice considerably attenuated gene overexpression in the liver of fetuses exposed to ECS throughout pregnancy. Inhibition of apoptosis by chemopreventive agents reflects their ability to counteract certain upstream signals, such as genotoxic damage, redox imbalances, and other forms of cellular stress that trigger apoptosis. On the other hand, enhancement of apoptosis is a double-edged sword, since it represents a protective mechanism in carcinogenesis but may contribute to the pathogenesis of other degenerative diseases. We suggest that stimulation of apoptosis by so many chemopreventive agents, as reported in the literature, may often reflect the occurrence of toxic effects at high doses.
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PMID:Modulation of apoptosis by cancer chemopreventive agents. 1613 21

Indole-3-carbinol (I3C) is a naturally occurring phytochemical which exerts a broad range of biological activities. The purpose of this study was to examine the effects of I3C on colon carcinogenesis, cell proliferation, cell-cycle progression and apoptosis, and on the levels of expression of several cell-cycle control molecules. We used a long-term rat model by using azoxymethane (AOM) to induce tumors (adenomas and adenocarcinomas) in the colon. In the present study, we found that after AOM injection, the treatment of male F344 rats with 0.01 and 0.05% I3C caused a significant increase in the tumor multiplicity of adenocarcinomas by 2.2- (P<0.05 for 0.01% I3C) and 2.1-fold (P<0.0002 for 0.05% I3C) respectively, when compared to the control rats. In addition, the tumor multiplicity of adenoma plus adenocarcinoma and the volume of adenocarcinoma were also increased by 2.0- (P<0.00001) and 2.1-fold (P<0.05) respectively, compared to the control. I3C significantly increased the proliferating cell nuclear antigen labeling index (PCNA LI) (P<0.008) and decreased the apoptotic index (P<0.05) of the colon adenocarcinoma. In contrast, in HCT 116 and HT29 human colon carcinoma cells, I3C inhibited growth and induced G1-phase cell-cycle arrest and apoptosis. Furthermore, I3C caused approximately a 2- to 4-fold increase in the cellular levels of p27KIP1 and p21CIP1 mRNA. These results suggest that I3C inhibits the growth of human colon carcinoma cells, at least in part, by inducing p27KIP1 and p21CIP1-mediated G1 cell-cycle arrest but dietary I3C promotes AOM-induced rat colon carcinogenesis by inhibiting the apoptosis of colon tumors. Therefore, the present study may provide further evidence for the ambivalent modulatory activity of I3C and this information may be useful when including I3C in cancer chemoprevention and/or extensive clinical therapy trials.
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PMID:Indole-3-carbinol inhibits the growth of human colon carcinoma cells but enhances the tumor multiplicity and volume of azoxymethane-induced rat colon carcinogenesis. 1621 Dec 36

The highlighted article in this issue by Tilton et al. (2005a) is an innovative approach to evaluate the modulation of estrogen receptor (ER) and aryl hydrocarbon (Ah)-receptor pathways as mechanisms underlying indole-3-carbinol (I3C) tumor promotion in rainbow trout (Onchorhynchus mykiss). I3C and its major in vivo component 3,3'-diindolylmethane (DIM) are potent tumor promoters that appear to target both of the aforementioned receptor pathways. However, the relative importance of I3C modulation of ER and AhR-dependent pathways in the promotion of rainbow trout hepatocarcinogenesis has not been established. Previously, researchers within this group reported that I3C promotes aflatoxin B1 (AFB1)-induced trout hepatocarcinogenesis post-initiation at low concentrations in the diet that induce the expression of vitellogenin, a downstream marker for the activation of ER-dependent pathways in fish. Furthermore, the promotional effects of I3C on AFB1 hepatocarcinogenesis in rainbow trout occur at concentrations that differentially induce vitellogenin, but not CYP1A expression. Interestingly, higher I3C concentrations induce the expression of both CYP1A and vitellogenin. Thus, the relative induction of vitellogenin and CYP1A expression, which are respective markers for activation of fish ER and AhR-mediated gene expression, suggest that these pathways may be important for tumor promotion by dietary I3C in trout. Understanding the complexities of I3C-mediated tumor promotion is essential from several perspectives. For example, there is the obvious need to increase our basic understanding of dietary modulation of carcinogenesis. In addition, I3C also exhibits significant antioxidant and cancer chemoprotective effects under certain experimental conditions and in certain models which have led to its recent marketing as a dietary supplement, as well as its development as a possible chemopreventive agent in humans.
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PMID:Using salmonid microarrays to understand the dietary modulation of carcinogenesis in rainbow trout. 1619 72


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