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

The biological characteristics of right-sided colon cancer were examined in 74 colon cancers with regard to clinicopathological parameters, proliferative activity and p53 expression. Significant differences between right-sided and left-sided colon cancer were found in age, tumor size, histological type and lymphatic vessel invasion. The proliferating cell nuclear antigen labeling index did not significantly differ between the two cancers. The frequency of p53 overexpression was lower in the former than in the latter. The results suggested that right-sided colon cancer did not differ from left-sided colon cancer in proliferative activity except for its tendency to be locally advanced and to differ in carcinogenesis.
 ...
PMID:The biological and clinicopathological characteristics of right-sided colon cancer. 1094 28

Theaflavin (TF-1), theaflavin-3-monogallate and theaflavin-3'-monogallate mixture (TF-2), and theaflavin-3,3'-digallate (TF-3) are the major black tea polyphenols. Here we compared the effects of these polyphenols on cell growth, apoptosis, and gene expression in normal and cancerous cells. We showed that TF-2 (10-50 microM) inhibited the growth of SV40 transformed WI38 human cells (WI38VA) and Caco-2 colon cancer cells but had little effect on the growth of their normal counterparts. The IC50s of TF-2 for the growth inhibition of WI38 and WI38VA cells were, respectively, 300 and 3 microM. The other two black tea polyphenols, TF-1 and TF-3, did not exhibit such differential growth-inhibitory effect. TF-2, but not TF-1 or TF-3, induced apoptosis in transformed WI38VA cells but not in normal WI38 cells, suggesting that apoptosis was responsible, at least in part, for the differential growth-inhibitory effect of TF-2. Cox-2 has been implicated in intestinal carcinogenesis. Among the tea polyphenols tested, TF-2 and, to a lesser degree, (-)-epigallocatechin gallate inhibited cyclooxygenase (Cox)-2 gene expression. TF-2 at 50 microM completely blocked the serum-induced Cox-2 gene expression at both mRNA and protein level. Other genes, including c-fos, c-myc, thymidine kinase, proliferating cell nuclear antigen, BRCA1, BRCA2, and Cox-1, were not significantly affected by TF-2. These findings suggest that TF-2 may be responsible, at least in part, for the chemopreventive activity in black tea extracts.
 ...
PMID:Differential effects of theaflavin monogallates on cell growth, apoptosis, and Cox-2 gene expression in cancerous versus normal cells. 1110 14

The mechanism behind hormone dependent growth of breast cancer is presently not well understood. We show that the HES-1 protein level in the breast cancer cell lines T47D and MCF-7 is down regulated by 17beta-estradiol treatment. This regulation could be reversed by addition of the anti-estrogens 4OH tamoxifen, raloxifen and Imperial Chemical Industries (ICI) 182,780. In T47D cells with inducible exogenous HES-1 expression, induced expression of HES-1 protein prevented the proliferative effect of 17beta-estradiol and subsequent up regulation of proliferating cell nuclear antigen (PCNA). An inverse correlation between the HES-1 and PCNA protein levels respectively was found in colon cancer cell lines. These findings point to a potential role of HES-1 as a tumor suppressor in epithelial cells, and as a mediator of 17beta-estradiols proliferative effect on breast cancer cells.
 ...
PMID:The Hairy and Enhancer of Split homologue-1 (HES-1) mediates the proliferative effect of 17beta-estradiol on breast cancer cell lines. 1112 27

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the incidence of colon cancer, but their use is limited by toxicity in the gastrointestinal tract. The coupling of a nitric oxide-releasing moiety to NSAIDs strongly reduces these side effects. We demonstrated that the NO-releasing sulindac (nitrosulindac) has much more potent effects on colon adenocarcinoma cell lines compared to sulindac. Moreover, it could inhibit the growth of cells in soft agar experiments, demonstrating the antineoplastic activity at low concentration of nitrosulindac. However, this reduction in the growth of colon cancer cells seemed to be independent of the classical apoptosis pathway and could be explained by a cytostatic effect. Nitrosulindac caused a light perturbation of the cell cycle parameters not linked to a modification of the levels of p21 or the proliferating cell nuclear antigen. Moreover, neither sulindac, nor nitrosulindac, were able to inhibit the NF-kappa B pathway. These data suggested that nitrosulindac could be a better solution compared to other NSAIDs in the treatment of colon cancer.
 ...
PMID:Antiproliferative effects of nitrosulindac on human colon adenocarcinoma cell lines. 1139 74

Although the incidence of colon cancer increases with advancing age, reasons for this increase are not fully understood. Earlier studies have demonstrated that in Fischer-344 rats, aging is associated with increased crypt cell production in the colon, an event considered to be central to the initiation of carcinogenesis. Apoptosis also plays a critical role in the development and progression of colon cancer. Therefore, we have examined the age-related changes in proliferation and apoptosis in the colonic mucosa of 4-5, 12-14, and 22-24 month-old Fischer-344 rats. We have observed that proliferative activity in the colon, as assessed by proliferating cell nuclear antigen immunoreactivity, is higher (50-80%) in 12-14 and 22-24 month-old rats than in their 4-6 month-old counterparts. In contrast, the number of apoptotic cells, (as determined by TdT-mediated dUTP nick-end labeling assay) in the colonic mucosa of 12-14 and 22-24 month-old rats are considerably lower (50-60%) than in 4-6 month-old animals. These changes are accompanied by a concomitant reduction (75%) in pro-apoptotic Bak and stimulation (200%) of anti-apoptotic Bcl-xL levels. Since activation of caspases is associated with initiation and maintenance of apoptosis, we also analyzed the levels of pro and active forms of caspase-3, 8 and 9. The levels of active forms of caspase-3, 8 and 9 are found to be considerably (60-80%) lower in the colonic mucosa of 22-24 month-old rats, compared to their younger counterparts. This is accompanied by decreased cleavage of poly(ADP-ribose) polymerase, a substrate for caspases. In conclusion, our data show that aging enhances proliferation, but attenuates apoptosis in the colonic mucosa. These changes may partly be responsible for the age-related rise in colorectal cancer.
 ...
PMID:Aging is associated with increased proliferation and decreased apoptosis in the colonic mucosa. 1155 85

Although a major effect of p21, a cyclin-dependent kinase inhibitor, is considered to be exerted during G(1) phase of the cell cycle, p21 gene knock-out studies suggested its involvement in G(2)/M checkpoint as well. Here we demonstrate evidence that p21 is required for the cell cycle arrest at G(2) upon DNA damage. We found that expression of wild-type p21 (p21(WT)), not mutant p21 (p21(PCNA-)) lacking the interaction with proliferating cell nuclear antigen (PCNA), caused G(2) cell cycle arrest in p53-deficient DLD1 colon cancer cell line after the DNA damage by treatment with cis-diamminedichloroplatinum (II). We also found that p21(WT) was associated with Cdc2/cyclin B1 together with PCNA. Furthermore, coimmunoprecipitation experiments revealed that PCNA interacted with Cdc25C at the G(2)/M transition, and this interaction was abolished when p21(WT) was expressed presumably due to the competition between p21(WT) and Cdc25C in the binding to PCNA. These findings suggest that p21 plays a regulatory role in the maintenance of cell cycle arrest at G(2) by blocking the interaction of Cdc25C with PCNA.
 ...
PMID:Involvement of the interaction between p21 and proliferating cell nuclear antigen for the maintenance of G2/M arrest after DNA damage. 1155 5

High intakes of dietary fiber or resistant starches have been associated with a lower incidence of colon cancers. Because short-chain fatty acids (SCFA) such as butyrate are produced in the colonic lumen by the bacterial fermentation of dietary fibers and resistant starches, we hypothesized that SCFA may inhibit the development of invasive human colon cancers. To test this hypothesis, primary human invasive colonocytes were isolated from fresh surgical specimens and treated with 0.01 mol/L acetate, propionate or butyrate; cell invasion, cell adhesion, F-actin polymerization, urokinase plasminogen activator (uPA), tissue inhibitor matrix metalloproteinase (TIMP)-1, TIMP-2 and mutant p53, Bcl-2, Bax, p21 and proliferating cell nuclear antigen (PCNA) protein expression levels were examined. Although each of the SCFA tested significantly reduced primary cell invasion, butyrate was the most potent, inhibiting primary invasive human colon cancer invasion by 54% (P < 0.0001). The effects of SCFA on primary cell invasion appeared to be independent of cell adhesion and F-actin polymerization but dependent on the inhibition of uPA (P < 0.05) and the stimulation of TIMP-1 and TIMP-2 activities (P < 0.05). Protein expression levels of mutant p53, p21, Bax, Bcl-2 and PCNA were significantly altered by each of the SCFA tested (P < 0.05). These data indicate that SCFA inhibit invasive human colon cancer by modulating proteolytic uPA and antiproteolytic TIMP-1 and TIMP-2 activities, but their mechanisms of action on tumor suppression, apoptosis and growth arrest may differ.
 ...
PMID:Short-chain fatty acids inhibit invasive human colon cancer by modulating uPA, TIMP-1, TIMP-2, mutant p53, Bcl-2, Bax, p21 and PCNA protein expression in an in vitro cell culture model. 1169 45

The resistance of advanced colorectal cancers to therapy is often related to mutations in the p53 tumor suppressor gene. Because somatostatin (SRIF) receptors (ssts) are present in colorectal carcinomas, the treatment with targeted cytotoxic SRIF analogue AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to octapeptide SRIF carrier RC-121, may overcome this resistance by producing a higher concentration of the cytotoxic agent in the tumors. Four colon cancer cell lines, HCT-116 and LoVo expressing wild-type p53, and HCT-15 and HT-29 with mutated p53, were investigated. HCT-116, HCT-15, and HT-29, but not LoVo possess functional ssts. We analyzed changes in p53, p21, and proliferating cell nuclear antigen (PCNA) concentrations in these cells in vitro by immunoblotting after exposure to AN-238, its radical AN-201, or doxorubicin (DOX). Equitoxic doses of AN-238, AN-201, or DOX affected p53, p21, and PCNA differently. Analysis of the p21:p53 ratios revealed that DOX increased p53 levels, but most of p53 was mutated and inactive, whereas AN-238 produced smaller changes in p53 concentrations but enhanced its activity. In HCT-15 cells, PCNA:p21 ratios, which are indicators of proliferation and repair processes, remained unchanged after exposure to AN-238 but were increased by DOX. In vivo studies in nude mice demonstrated that AN-238, AN-201, and DOX were equally effective on HCT-116 tumors that express wild-type p53. However, AN-238 also inhibited the growth of HCT-15 and HT-29 cancers that express mutant p53, whereas AN-201 and DOX showed no effect. None of the compounds could suppress the proliferation of LoVo tumors that lack functional ssts. In conclusion, cytotoxic SRIF analogue AN-238 inhibits the growth of experimental colon cancers that express ssts, regardless of their p53 status.
 ...
PMID:Targeted cytotoxic somatostatin analogue AN-238 inhibits somatostatin receptor-positive experimental colon cancers independently of their p53 status. 1183 May 33

The present study was designed to investigate the efficacy of combination gene therapy using adenoviral vectors expressing gene products shown to possess apoptotic activity: E2F-1 (Ad-E2F-1) and a C-terminal deletion mutant of p21(WAF1/cIP1) (Ad-p21(-PCNA)), on growth inhibition and apoptosis of human colon cancer cells in vitro and in vivo. Marked E2F-1 and p21(-PCNA) overexpression in response to adenovirus infection was evident by Western blot analysis. IC(25) concentrations of each virus were used for each treatment in vitro to detect cooperative effects on cell death. Coexpression of E2F-1 and p21(-PCNA) resulted in an additive effect on cell death compared to infection with either virus alone. Cell cycle analysis, poly(ADP-ribose) polymerase (PARP) cleavage and analysis of cell morphology also revealed that coinfection with both Ad-E2F-1 and Ad-p21(-PCNA) enhanced cellular apoptosis compared to either virus alone. Interestingly, E2F-1 protein expression was markedly enhanced in the E2F-1/p21(-PCNA) adenovirus combination compared to Ad-E2F-1 infection alone. However, these same effects were not evident in cells coinfected with Ad-E2F-1 and an adenovirus expressing wild-type human p21(WAF1/CIP1) (Ad-p21(WT)). The increase in E2F-1 expression with coexpression of E2F-1 and p21(-PCNA) was not a result of increased E2F-1 protein stability, but was related to increased transcriptional activity from the CMV promoter. Cell cycle analysis revealed G1 arrest 72 hours following single-gene therapy with either the wild-type or mutant p21, whereas increased accumulation of cells in G2/M phase was demonstrated in the E2F-1-overexpressing cells. In the combined therapies, E2F-1/p21(-PCNA) treatment still resulted in G1 arrest, but E2F-1 was able to counteract the G1 arrest when coinfected with p21(WT). These results provide further evidence of the importance of the p21:PCNA-binding domain in mediating the complex cell cycle interaction between E2F-1 and p21. Simultaneous intratumoral injection of Ad-E2F-1 and Ad-p21(-PCNA) dramatically reduced tumor burden of SW620 xenografts compared to either treatment alone in our in vivo model but not in HT-29 colon cancer xenografts. When combined with Ad-p21(-PCNA), E2F-1 adenovirus therapy resulted in approximately 95% decrease in tumor volume of SW620 tumor xenografts compared with controls (P<.05). In conclusion, although simultaneous delivery of E2F-1 and p21(-PCNA) transgenes results in increased E2F-1 expression and enhanced apoptosis of both SW620 and HT-29 colon cancer cells in vitro, this combination was only effective in the treatment of SW620 metastatic colon cancer in vivo. This may represent a potentially useful combination gene therapy strategy for metastatic colon cancer.
 ...
PMID:C-terminal deletion mutant p21(WAF1/CIP1) enhances E2F-1-mediated apoptosis in colon adenocarcinoma cells. 1196 68

Laboratory and epidemiological studies suggest that butyrate, a metabolic product of microbial fermentation of dietary fibre, and aspirin, a non-steroidal antiphlogistic drug, both reduce the risk of developing colon cancer. Notably, few data exist on potential interactions of these two substances. In this study, the effects of a butyrate-aspirin combination on human colon cancer cells were compared with treatment with aspirin or butyrate alone. Both substances decreased proliferation and induced differentiation and apoptosis. Butyrate reduced mutant p53 expression, whereas aspirin did not affect p53 expression. Butyrate-induced apoptosis correlated with an increase in Bak expression and a decrease in the expression of Bcl-XL. Aspirin had no effect on the investigated apoptosis-controlling factors. The antiproliferative and pro-apoptotic effects of the butyrate-aspirin combination were markedly enhanced. The combination resulted in a stronger decrease in the expression of PCNA and cdk2. Our data suggest that the anticarcinogenic effect of aspirin might effectively be augmented by combination with the short-chain fatty acid butyrate.
 ...
PMID:Butyrate and aspirin in combination have an enhanced effect on apoptosis in human colorectal cancer cells. 1213 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>