UMLS:C0699790 - FACTA Search

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies were conducted to determine the chemopreventive efficacy of several types of tea extracts on azoxymethane-induced colon cancer in male F344 rats. After determining the maximally tolerated dosage of the tea products, their effect in a colon cancer model was investigated. Groups of 36 male F344 rats received 2 subcutaneous doses of 15 mg/kg azoxymethane (AOM) at Weeks 6 and 7. Experimental groups also received as drinking fluids 3600 ppm of black or green tea extracts, 1800 ppm of EGCG, or 1800 ppm of black or green tea polyphenols beginning at 5 weeks of age. Additional groups drank a lower dose of 360 ppm of the five tea products. The experiments were terminated 43 weeks after the first tea exposure. No evidence of toxicity was observed since the body weight gain of all groups was similar. The rats given AOM had carcinoma of the small intestine and of the colon, classified histologically as in situ carcinoma, exophytic, invasive, and Peyer's patch carcinoma. In the small intestine, most of the neoplasms were classified as invasive, but in the colon, most were exophytic. The various tea products failed to produce a significant difference in the incidence of the several types of colon and small intestine carcinoma. The multiplicity of colon cancers ranged from 1.2-2.8 in all groups. The group on 3600 ppm of green tea had a significantly higher tumor multiplicity than the control group on AOM and water. Also, the group on 3600 ppm of green tea had a significantly higher tumor multiplicity than the group on 360 ppm. The tea products did not affect the development aspects of the tumors in most groups. The mechanisms underlying these findings rest on the fact that azoxymethane is metabolized mainly by cytochrome P450 2E1, and this enzyme system is not affected by tea.
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PMID:Effect of tea extracts, polyphenols, and epigallocatechin gallate on azoxymethane-induced colon cancer. 942 Dec 13

Epigallocatechin gallate (EGCg) and theaflavins, a major constituent of green tea infusion and the constituents of black tea, respectively, were found to inhibit matrix metalloproteinases (MMPs) which are intimately associated with tumor invasion and metastasis. EGCg and related polyphenols exhibited apoptosis-inducing activity for several cancer cell lines including human stomach and colon cancer cells. Comparison of the activity of these compounds revealed the importance of the number and the steric disposition of hydroxyl groups. A pyrogallol-type structure in a molecule is a minimum requirement for apoptosis induction of catechin compounds and that in the B ring has an important role in the activity. These data would provide useful information for designing anti-cancer agents on the basis of anti-inhibitory activity for MMPs and/or apoptosis-inducing activity.
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PMID:Tea catechins and related polyphenols as anti-cancer agents. 1123 4

(-)-Epigallocatechin gallate (EGCG), a major constituent of green tea, has been shown to exhibit anti-cancer activity. Sulindac is also well known as a cancer-preventive agent against colon cancer, but its usage is restricted because of its adverse effects, as exemplified by gastrointestinal bleeding. In the present study, we examined whether a combination of EGCG and sulindac shows synergistic effects for cancer-preventive activity for rat colon carcinogenesis induced by azoxymethane (AOM); we examined the number of aberrant crypt foci (ACF) representing preneoplastic lesions, the argyrophilic nucleolar organizer region (AgNOR) as an indicator of cell proliferation, and the incidence of apoptosis. The AOM treatment induced an average of 46.2+/-4.9 ACF/colon, and sulindac and EGCG significantly reduced the incidence of ACF/colon to 21.4+/-3.4 and 19.5+/-5.8, respectively (P<0.01). The co-treatment with EGCG and sulindac resulted in significantly reduced ACF formation (10.0+/-3.2; P<0.01). The results of the AgNOR analysis indicated that the treatment with EGCG and/or sulindac suppressed AOM-induced cell proliferation. The present results also revealed that the combination of EGCG and sulindac synergistically enhanced apoptosis significantly (P<0.01). Thus, our findings suggest that EGCG with sulindac synergistically suppresses ACF formation by enhancing apoptosis and, therefore, that EGCG is a suitable candidate for use in combination with cancer-preventive agents, such as sulindac, to reduce their adverse effects.
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PMID:Synergistic effects of (-)-epigallocatechin gallate with sulindac against colon carcinogenesis of rats treated with azoxymethane. 1180 30

(-)-Epigallocatechin gallate (EGCG) and (-)-epigallocatechin (EGC) are major green tea catechins with antioxidant and anticancer activities. In this study, we characterized the glucuronidation of EGCG and EGC in human, mouse, and rat microsomes and by nine different human UGT 1A and 2B isozymes expressed in insect cells. Six EGCG and EGC glucuronides were biosynthesized, and their structures were identified for the first time. (-)-EGCG-4"-O-glucuronide was the major EGCG glucuronide formed in all incubations. The catalytic efficiency (V(max)/K(m)) for (-)-EGCG-4"-O-glucuronide formation followed the order: mouse intestine > mouse liver > human liver > rat liver >> rat small intestine. The UGT-catalyzed glucuronidation of EGC was much lower than that of EGCG. The V(max)/K(m) for (-)-EGC-3'-O-glucuronide followed the following order: mouse liver > human liver > rat liver > rat and mouse small intestine. Human UGT1A1, 1A8, and 1A9 had high activities with EGCG. UGT1A8, an intestine-specific UGT, had the highest V(max)/K(m) for EGCG but low activity with EGC. Mice appeared to be more similar to humans than rats to humans in the glucuronidation of EGCG and EGC. Some of these catechin glucuronides retained the activities of their parent compounds in radical scavenging and in inhibiting the release of arachidonic acid from HT-29 human colon cancer cells. These results provide foundations for understanding the biotransformation and biological activities of tea catechins.
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PMID:Glucuronides of tea catechins: enzymology of biosynthesis and biological activities. 1264 72

The IGF/IGF-1R system, which includes the IGF, IGF-1R, and IGFBPs proteins, plays an important role in the development and growth of colorectal cancer. We previously reported that in the HT29 human colon cancer cell line EGCG, the major biologically active component of green tea, inhibits activation of the RTKs EGFR, HER2, and HER3, and that this is associated with inhibition of multiple downstream signaling pathways. Since IGF-1R is also a RTK, in this study we examined the effects of EGCG on the activity of IGF/IGF-1R system in human colon cancer cells. We found that the colon cancer cell lines Caco2, HT29, SW837, and SW480 express high levels of the IGF-1R receptor, and that both SW837 and SW480 cells display constitutive activation of this receptor. Treatment of SW837 cells with 20 microg/ml of EGCG (the IC50 concentration for growth inhibition) caused within 6 h a decrease in the phosphorylated (i.e., activated) form of the IGF-1R protein. At 12 h, there was a decrease in the levels of both IGF-1 protein and mRNA and within 3-6 h there was an increase in the levels of both IGFBP-3 protein and mRNA. The increased expression of the latter protein was sustained for at least 48 h. When SW837 cells were treated with EGCG for a longer time, i.e., 96 h, a very low concentration (1.0 microg/ml) of EGCG also caused inhibition of activation of IGF-1R, a decrease in the IGF-1 protein, and an increase in the IGFBP-3 protein. EGCG also caused a decrease in the levels of mRNAs that encode MMPs-7 and -9, proteins that proteolyze IGFBP-3. In addition, treatment with EGCG caused a transient increase in the expression of TGF-beta2, an inducer of IGFBP-3 expression. These findings expand the roles of EGCG as an inhibitor of critical RTKs involved in cell proliferation, providing further evidence that EGCG and related compounds may be useful in the chemoprevention or treatment of colorectal cancer.
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PMID:EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells. 1605 20

Epigallocatechin-3-gallate (EGCG; molecular formula: C22H18011)is the most abundant catechin in green tea (Camellia sinensis Theaceae). Both EGCG and green tea have been shown to have cancer-preventive activity in a number of animal models, and numerous mechanisms have been proposed based on studies with human cell lines. EGCG has been shown to undergo extensive biotransformation to yield methylated and glucuronidated metabolites in mice, rats, and humans. In the present study, we determined the concentration-dependent uptake of EGCG by HT-29 human colon cancer cells (20-600 microM) and the dose dependence of EGCG plasma and tissue levels after a single dose of EGCG (50-2000 mg/kg i.g.) to male CF-1 mice. The cytosolic levels of EGCG were linear with respect to extracellular concentration of EGCG after treatment of HT-29 cells for 2 h (915.3-6851.6 microg/g). In vivo, EGCG exhibited a linear dose relationship in the plasma (0.03-4.17 microg/ml), prostate (0.01-0.91 microg/g), and liver (0.09-18.3 microg/g). In the small intestine and colon, however, the levels of EGCG plateaued between 500 and 2000 mg/kg i.g. These results suggest that absorption of EGCG from the small intestine is largely via passive diffusion; however, at high concentrations, the small intestinal and colonic tissues become saturated. The levels of 4''-O-methyl-EGCG and 4',4''-di-O-methyl-EGCG parallel those of EGCG with respect to dose. The present study provides information with respect to what concentrations of EGCG are achievable in mice and may guide dose selection for future cancer chemoprevention studies with EGCG.
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PMID:Dose-dependent levels of epigallocatechin-3-gallate in human colon cancer cells and mouse plasma and tissues. 1620 66

Increased expression of COX-2 appears to play an important role in the development of colorectal cancer. The level of COX-2 expression is regulated by various factors including activation of members of the EGFR family of RTKs. We previously reported that in HT29 human colon cancer cells EGCG, the major biologically active component of green tea, inhibits activation of two members of this family, EGFR and HER2, and multiple downstream signaling pathways. In this study we examined the effects of EGCG on the HER3 RTK and on COX-2 expression in the SW837 human colon cancer cell line that expresses a high level and constitutive activation of HER3 and also expresses a high level of COX-2. Treatment of these cells with 20 microg/ml of EGCG (the IC50 concentration for growth inhibition) caused, within 6 hours, a decrease in the phosphorylated (i.e. activated) forms of not only EGFR and HER2, but also HER3. At 6 to 12 hours there was a decrease in the phosphorylated forms of the downstream signaling proteins ERK and Akt. Within 6 to 12 hours there was a decrease in cellular levels of both COX-2 protein and mRNA, and within 48 hours the cells displayed apoptosis. Reporter assays indicated that EGCG inhibited the transcriptional activities of the COX-2, AP-1, and NF-kappaB promoters. EGCG also caused a decrease in production of PGE2, a major product of COX-2. With a longer incubation time, 96 hours, a very low dose (1.0 microg/ml) of EGCG also caused inhibition of cell growth, inhibition of activation of EGFR, HER2, and HER3, a decrease in the levels of COX-2 and Bcl-xL proteins, and apoptosis. These results provide the first evidence that a low concentration of EGCG can inhibit activation of, at least, three members of the EGFR family of RTKs, and also inhibit COX-2 expression in colon cancer cells. These findings extend our previous evidence that EGCG may be useful in the chemoprevention and/or treatment of colorectal cancer.
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PMID:EGCG inhibits activation of HER3 and expression of cyclooxygenase-2 in human colon cancer cells. 1641 3

EGCG [(-)epigallocatechin-3-gallate], a green tea-derived polyphenol, has been shown to suppress cancer cell proliferation, and interfere with the several signaling pathways and induce apoptosis. Practically, there is emerging evidence that EGCG has a potential to increase the efficacy of chemotherapy in patients. We hypothesized that EGCG may exert cell cytotoxicity through modulating AMPK (AMP-activated protein kinase) followed by the decrease in COX-2 expression. EGCG treatment to colon cancer cells resulted in a strong activation of AMPK and an inhibition of COX-2 expression. The decreased COX-2 expression as well as prostaglandin E(2) secretion by EGCG was completely abolished by inhibiting AMPK by an AMPK inhibitor, Compound C. Also, the activation of AMPK was accompanied with the reduction of VEGF (vascular endothelial growth factor) and glucose transporter, Glut-1 in EGCG-treated cancer cells. These findings support the regulatory role of AMPK in COX-2 expression in EGCG-treated cancer cells. Furthermore, we have found that reactive oxygen species (ROS) is an upstream signal of AMPK, and the combined treatment of EGCG and chemotherapeutic agents, 5-FU or Etoposide, exert a novel therapeutic effect on chemo-resistant colon cancer cells. AMPK, a molecule of newly defined cancer target, was shown to control COX-2 in EGCG-treated colon cancer cells.
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PMID:Apoptotic effect of EGCG in HT-29 colon cancer cells via AMPK signal pathway. 1679 20

Nuclear factor kappa B (NF-kappaB) is a redox-associated transcription factor that is involved in the activation of survival pathways. We have previously shown that deoxycholate (DOC) activates NF-kappaB in hepatocytes and colon epithelial cells and that persistent exposure of HCT-116 cells to increasing concentrations of DOC results in the constitutive activation of NF-kappaB, which is associated with the development of apoptosis resistance. The mechanisms by which DOC activates NF-kappaB in colon epithelial cells, and whether natural antioxidants can reduce DOC-induced NF-kappaB activation, however, are not known. Also, it is not known if DOC can generate reactive oxygen species within mitochondria as a possible pathway of stress-related NF-kappaB activation. Since we have previously shown that DOC activates the NF-kappaB stress-response pathway in HCT-116 cells, we used this cell line to further explore the mechanisms of NF-kappaB activation. We found that DOC induces mitochondrial oxidative stress and activates NF-kappaB in HCT-116 cells through multiple mechanisms involving NAD(P)H oxidase, Na+/K+-ATPase, cytochrome P450, Ca++ and the terminal mitochondrial respiratory complex IV. DOC-induced NF-kappaB activation was significantly (P < 0.05) inhibited by pre-treatment of cells with CAPE, EGCG, TMS, DPI, NaN3, EGTA, Ouabain and RuR. The NF-kappaB-activating pathways, induced by the dietary-related endogenous detergent DOC, provide mechanisms for promotion of colon cancer and identify possible new targets for chemoprevention.
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PMID:Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells. 1688 64

(-)-Epigallocatechin gallate (EGCG), a major biologically active constituent of green tea, inhibits activation of the epidermal growth factor (EGF) receptor (EGFR) and downstream signaling pathways in several types of human cancer cells, but the precise mechanism is not known. Because several plasma membrane-associated receptor tyrosine kinases (RTK) including EGFR are localized in detergent-insoluble ordered membrane domains, so-called "lipid rafts," we examined whether the inhibitory effect of EGCG on activation of the EGFR is associated with changes in membrane lipid order in HT29 colon cancer cells. First, we did cold Triton X-100 solubility assays. Phosphorylated (activated) EGFR was found only in the Triton X-100-insoluble (lipid raft) fraction, whereas total cellular EGFR was present in the Triton X-100-soluble fraction. Pretreatment with EGCG inhibited the binding of Alexa Fluor 488-labeled EGF to the cells and also inhibited EGF-induced dimerization of the EGFR. To examine possible effects of EGCG on membrane lipid organization, we labeled the cells with the fluorescent lipid analogue 1, 1'-dihexadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, which preferentially incorporates into ordered membrane domains in cells and found that subsequent treatment with EGCG caused a marked reduction in the Triton X-100-resistant membrane fraction. Polyphenon E, a mixture of green tea catechins, had a similar effect but (-)-epicatechin (EC), the biologically inactive compound, did not significantly alter the Triton X-100 solubility properties of the membrane. Furthermore, we found that EGCG but not EC caused dramatic changes in the function of bilayer-incorporated gramicidin channels. Taken together, these findings suggest that EGCG inhibits the binding of EGF to the EGFR and the subsequent dimerization and activation of the EGFR by altering membrane organization. These effects may also explain the ability of EGCG to inhibit activation of other membrane-associated RTKs, and they may play a critical role in the anticancer effects of this and related compounds.
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PMID:The inhibitory effect of (-)-epigallocatechin gallate on activation of the epidermal growth factor receptor is associated with altered lipid order in HT29 colon cancer cells. 1761 11

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