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)

Reovirus selectively replicates in and destroys cancer cells with an activated Ras signaling pathway. In this study, we evaluated the feasibility of using reovirus (serotype 3, strain Dearing) as an antihuman colon and ovarian cancer agent. In in vitro studies, reovirus infection in human colon and ovarian cell lines was assessed by cytopathic effect as detected by light microscopy, [(35)S]Methionine labeling of infected cells for viral protein synthesis and progeny virus production by plaque assay. We observed that reovirus efficiently infected all five human colon cancer cell lines (Caco-2, DLD-1, HCT-116, HT-29, and SW48) and four human ovarian cancer cell lines (MDAH2774, PA-1, SKOV3, and SW626) which were tested, but not a normal colon cell line (CCD-18Co) or a normal ovarian cell line (NOV-31). We also observed that the Ras activity in the human colon and ovarian cancer cell lines was elevated compared with that in normal colon and ovarian cell lines. In animal models, intraneoplastic as well as i.v. inoculation of reovirus resulted in significant regression of established s.c. human colon and ovarian tumors implanted at the hind flank. Histological studies revealed that reovirus infection in vivo was restricted to tumor cells, whereas the surrounding normal tissue remained uninfected. Additionally, in an i.p. human ovarian cancer xenograft model, inhibition of ascites tumor formation and the survival of animals treated with live reovirus was significantly greater than of control mice treated with UV-inactivated reovirus. Reovirus infection in ex vivo primary human ovarian tumor surgical samples was also confirmed, further demonstrating the potential of reovirus therapy. These results suggest that reovirus holds promise as a novel agent for human colon and ovarian cancer therapy.
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PMID:Oncolytic reovirus against ovarian and colon cancer. 1191 42

Exposure of three colon cancer cell lines, SW480, DLD-1, and COLO201, to arsenic trioxide in the medium induced a marked concentration-dependent suppression of cell growth. The intracellular contents of reduced glutathione (GSH) in these cell lines tended to be inversely correlated with the sensitivity of the cells to arsenic trioxide. Among the cell lines, SW480 cells underwent apoptosis at the low arsenic trioxide concentration of 2 microM, which was prevented by pretreatment of the cells with N-acetylcysteine and was enhanced by buthionine sulfoximine. The production of reactive oxygen intermediates which were examined by 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA), increased with time after treatment with arsenic trioxide. The apoptosis was executed by the activation of caspase 3, which was shown by Western blot, enzymatic activity, and apoptosis inhibition assay. The mitochondrial membrane potential of adherent apoptotic SW480 cells and the cells from intermediate layer separated by density gradient centrifugation, both of which showed the active form of caspase 3 by Western blot analysis, was not lost. The overexpression of Bcl-2 protein in SW480 cells could not prevent the apoptosis induced by the treatment with arsenic trioxide. All these findings indicate that arsenic trioxide-induced apoptosis in SW480 cells is executed by the activation of caspase 3 without mediating by mitochondria under the overproduction of reactive oxygen species.
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PMID:Arsenic trioxide-induced apoptosis through oxidative stress in cells of colon cancer cell lines. 1200 85

A novel inhibitor for anchorage-independent growth of tumor cells was isolated from the culture broth of a fungal strain. The producing strain TP-F0213 was identified as Penicillium aurantiogriseum Dierckx based on the taxonomic study. The compound designated anicequol was obtained by solvent extraction, HP-20 and silica gel chromatographies and recrystallization. The planar structure was elucidated by NMR analysis to be 16-acetoxy-3,7,11-trihydroxyergost-22-en-6-one. The absolute configuration was determined by the X-ray analysis of 3,7-bis-p-bromobenzoyl derivative. The carbon skeleton of anicequol has the same absolute configuration as ergostane and the configurations of substituents are 3beta, 5alpha, 7beta, 11beta, 16beta and 24S. Anicequol inhibited the anchorage-independent growth of human colon cancer DLD-1 cells with the IC50 of 1.2 microM whereas the IC50 against anchorage-dependent growth was 40 microM.
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PMID:Anicequol, a novel inhibitor for anchorage-independent growth of tumor cells from Penicillium aurantiogriseum Dierckx TP-F0213. 1206 44

A new non peptidic farnesyltransferase inhibitor, RPR-115135, in combination with 5-FU was studied in 10 human colon cancer cell lines (HCT-116, RKO, DLD-1, Colo-320, LoVo, SW-620, HT-29, HCT-15, Colo-205 and KM-12) carrying several mutations but well characterized for p53 and Ras status. We found that there was a slight tendency (not statistically significant) for the p53 inactivated cells to be less sensitive to 5-FU after 6 days continuous treatment. Simultaneous administration of RPR-115135 and 5-FU, at subtoxic concentrations, resulted in a synergistic enhancement of 5-FU cytotoxicity in the p53 wildtype cells (HCT-116, RKO, DLD-1, Colo-320, LoVo). In the p53 mutated cells (SW-620, HT-29, HCT-15, Colo-205, KM-12) the effect was very complicated. In HCT-15 the combination resulted in antagonism, in KM-12 in antagonism or in synergy (at different concentrations) and in SW-620, HT-29 and Colo-205 cells in synergy but only when 5-FU was administered at high concentrations. Growth inhibition could be accounted for on the basis of a specific cell cycle arrest phenotype (G2-M arrest), as assayed by flow cytometry, only in the p53 functioning cell lines. The combination RPR-115135 + 5-FU increases apoptotic events only in these cell lines. In the mutated cell lines no major alterations on cell cycle arrest phenotype and no induction of apoptosis was observed. Although RPR-115135 can potentiate the effect of 5-FU in cells in which p53 function is disrupted, these data suggest strongly that RPR-115135 significantly enhances the efficacy of 5-FU only when p53 is functioning.
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PMID:RPR-115135, a farnesyltransferase inhibitor, increases 5-FU- cytotoxicity in ten human colon cancer cell lines: role of p53. 1211 40

5-fluorouracil (5-FU) is an important antineoplastic agent that has proven to be effective in the treatment of colorectal cancer. However, one of the main obstacles to the clinical use of 5-FU is the acquisition of resistance to the drug by cancer cells. In vitro studies have demonstrated that the resistance to 5-FU is correlated with increased activity of thymidylate synthase (TS), whose gene has a E2F binding site in its promoter region. To understand the mechanisms through which cancer cells acquire resistance to 5-FU, human colon cancer-derived cell line DLD-1 and its subcloned cell line DLD-1/5-FU, which has acquired resistance to 5-FU, were compared by assessing their phosphorylation of retinoblastoma protein (pRb) and E2F-1 transcriptional activity. The level of pRb phosphorylation in the DLD-1/5-FU cells was higher than in the parental DLD-1cells. In parallel with the increased phosphorylation of pRb, E2F-1 transcriptional activity, which has been shown to be a result of E2F-1 dissociation from hyperphosphorylated pRb, was increased in the DLD-1/5-FU cells. Examination of the effect of E2F-1 decoy oligodeoxynucleotides (ODNs) on the proliferation of DLD-1/5-FU cells in the presence of 5-FU to confirm the importance of E2F-1 in the mechanisms of the acquisition of 5-FU resistance showed that DLD-1/5-FU cells transfected with E2F-1 decoy ODNs recovered their sensitivity to 5-FU. These results suggested that pRb and E2F-1 play important roles in the acquisition of 5-FU resistance by cancer cells and that cancer therapy targeting transcription factor E2F might be effective.
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PMID:Role of retinoblastoma protein and E2F-1 transcription factor in the acquisition of 5-fluorouracil resistance by colon cancer cells. 1211 26

The down-regulated in adenoma (DRA) gene is significantly down-regulated in adenomas and adenocarcinomas of the colon as well as in colon cancer cell lines. It is also mutated in the disease congenital chloride diarrhea, which is characterized by loss of chloride transport and diarrhea. We now show a second function for DRA relevant to colon tumorigenesis, i.e., growth suppression. Transfection of full-length DRA into various cell lines (DLD-1, HT-29, HCT-15, SW837, SW480, MCF-7, NIH3T3, CaSki, and HeLa) that lack endogenous DRA expression results in a reduced number of drug-resistant colonies compared with vector control, suggesting growth suppression by DRA. In addition, expression of DRA under the control of an inducible promoter reduced the growth rate of DLD-1 cells compared with cells not expressing DRA. The COOH-terminal cytoplasmic domain of DRA is required for growth suppression, but an in-frame deletion (DeltaVal317) that causes congenital chloride diarrhea and results in a loss of anion transport had no effect on growth suppression, indicating that anion transport and growth suppression are independent functions of DRA. One cell line, adenovirus-transformed HEK293, exhibited significant resistance to DRA-induced growth suppression, whereas the human papillomavirus-transformed cell lines, CaSki and HeLa, did not. E1A is an adenoviral protein required to transform HEK293 cells. DLD-1 cells that stably express 12S E1A are resistant to growth suppression by DRA, similar to HEK293 cells.
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PMID:The colon anion transporter, down-regulated in adenoma, induces growth suppression that is abrogated by E1A. 1220 65

PC-SPES is a mixture of eight herbs with antiproliferative activity in prostate cancer cell lines and antitumor effects in animal models of prostate cancer. In addition, evidence of clinical efficacy in advanced prostate cancer has been reported. PC-SPES has also been shown to have antitumor activity against several other cancer cell lines including breast and neuroepithelial cancer, melanoma, and leukemia cell lines. Because of these findings, we investigated the effects of PC-SPES in vitro in colon cancer cell lines SW480, SW620, and DLD-1 and in vivo in the Apc(min) mouse, a murine model for intestinal carcinogenesis. For the in vitro studies, colon cancer cell lines were exposed to an ethanolic extract of PC-SPES compared with a diluent control [ethanol < or = 0.3% (v/v)]. PC-SPES resulted in a marked suppression of cell proliferation in all colon cancer cells studied. PC-SPES (3 micro l/ml) caused a 95% inhibition of cell proliferation of the DLD-1 colon cancer cell line, and similar results were observed in the SW480 and SW620 colon cancer cell lines. Cell cycle analysis demonstrated a drastic (> or =60%) accumulation of cells in the G(2)-M phase with a concomitant decrease of cells in the G(0)-G(1) phase in all colon cancer cell lines studied after treatment with PC-SPES (1.5 micro l/ml for 48 h). Western blot analysis demonstrated a decrease in protein levels of beta-tubulin in the SW620 cell line exposed to PC-SPES. Terminal deoxynucleotidyl transferase-mediated nick end labeling analysis revealed an increase in apoptotic colon cancer cells incubated with PC-SPES. For the in vivo studies, female 4-5-week-old Apc(min) mice were randomized to two groups: a PC-SPES-treated group (n = 11) received 250 mg/kg/day (0.2 ml) PC-SPES via gastrointestinal gavage; and a control group (n = 10) received 0.2 ml of the vehicle solution (1.5% carboxymethylcellulose with 0.2% Tween 20) via gastrointestinal gavage. Both groups were treated five times a week for 10 weeks. After treatment, the gastrointestinal tract was dissected for polyp scoring by two observers blinded to treatment. The Apc(min) mice given PC-SPES had a 58% reduction in tumor number and a 56% decrease in tumor load. No effect on either food intake or body weight was observed in the treated versus sham groups. The present study is the first to report the potent activity of PC-SPES against colon cancer. Both cell cycle arrest and apoptosis occurred after treatment with PC-SPES. This suggests that the components of this herbal mixture, either independently or in combination, acted in colon cancer, resulting in a drastic effect on tumor initiation and tumor progression.
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PMID:PC-SPES inhibits colon cancer growth in vitro and in vivo. 1223 85

MUC2 is one of the major components of mucins that provide a protective barrier between epithelial surfaces and the gut lumen. We investigated possible alterations of MUC2 gene expression by p53 and p21(Sdi1/Waf1/Cip1) in a human colon cancer cell line, DLD-1, establishing subclones in which a tetracycline-regulatable promoter controls exogenous p53 and p21 expression. MUC2 mRNA more significantly increased in response to p53 than to p21. Unexpectedly, MUC2 expression was also induced in human osteosarcoma cells, U-2OS and Saos-2, by exogenous p53. We next performed a reporter assay to test the direct regulation of MUC2 gene expression by p53. Deletion and mutagenesis of the MUC2 promoter region showed that it contains two sites for transactivation by p53. Furthermore, an electrophoretic mobility shift assay indicated that p53 binds to those elements. We analyzed MUC2 expression in other cell types possessing a functional p53 after exposure to various forms of stress. In MCF7 breast cancer and A427 lung cancer cells, MUC2 expression was increased along with the endogenous p53 level by actinomycin D, UVC, and x-ray, but not in RERF-LC-MS lung cancer cells carrying a mutated p53. These results suggest that p53 directly activates the MUC2 gene in many cell types.
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PMID:Transcriptional activation of the MUC2 gene by p53. 1237 98

Hygrolidin family antibiotics showed selective cytotoxicity against both cyclin E- and cyclin A-overexpressing cells. Among them, hygrolidin was the most potent and inhibited growth of solid tumor-derived cell lines such as DLD-1 human colon cancer cells efficiently more than that of hematopoietic tumor cells and normal fibroblasts. FACS analysis revealed that hygrolidin increased cells in G1 and S phases in DLD-1 cells. While hygrolidin decreased amounts of cyclin-dependent kinase (cdk) 4, cyclin D, and cyclin B, it increased cyclin E and p21 levels. Hygrolidin-induced p21 bound to and inhibit cyclin A-cdk2 complex more strongly than cyclin E-cdk2 complex. Furthermore, hygrolidin was found to increase p21 mRNA in DLD-1 cells, but not in normal fibroblasts. Thus, hygrolidin inhibited tumor cell growth through induction of p21. In respect to p21 induction, inhibition of vacuolar-type (H+)-ATPase by hygrolidin was suggested to be involved.
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PMID:Hygrolidin induces p21 expression and abrogates cell cycle progression at G1 and S phases. 1237 37

We previously reported that the retinoic acid (RA) insensitivity of RARbeta induction is a general feature of human colon cancer cells (Biochem. Pharmacol., 59: 485-496, 2000). In the present investigation, we analyzed potential transcriptional defects associated with the expression of the RARbeta gene in colon cancer cells. Transfection of reporter constructs containing the RARbeta gene promoter as well as truncated fragments of the promoter showed a significant induction of reporter activity by RA treatment in RA-sensitive HCT-15 cells, but not in RA-resistant DLD-1 cells. The results suggest that the transcriptional defect of RARbeta expression may not be due to the presence of a specific cis-element in the RARbeta promoter. Next we examined whether coactivators and core-pressors of nuclear receptors were involved in the RA sensitivity of colon cancer cells. Transfection of coactivators such as CREB binding protein (CBP) and p300 up-regulated the RA-responsive element present in the RARbeta promoter (betaRARE) in DLD-1 cells up to the level in HCT-15, while coexpression of the nuclear receptor corepressor (NCoR) suppressed the betaRARE activity in HCT-15 cells. The expression level of CBP protein was consistently higher in HCT-15, while that of NCoR and Sin3A was higher in DLD-1 cells. Treatment with the histone deacetvlase inhibitor trichostatin A (TSA) increased both basal and RA-induced betaRARE activity in DLD-1, indicating that histone deacetylase is involved in the regulation of RARbeta gene expression. Taken together, our results show that differential function of coactivators and corepressors may determine the level of RARbeta induction that may mediate retinoid action in colon cancer cells.
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PMID:Role of coactivators and corepressors in the induction of the RARbeta gene in human colon cancer cells. 1239 82


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