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)

Soybeans are major dietary sources of saponins, which have been suggested as possible anticarcinogens. This study was performed to determine the effect of soybean saponins on cell proliferation, differentiation, and apoptosis in human colon cancer cells. HT-29 cells were incubated in various concentrations of saponins for 24, 48, and 72 hours. Cell growth and whole cell protein kinase C (PKC) activity were determined. Alkaline phosphatase activity and carcinoembryonic antigen level were measured as markers for cell differentiation. Apoptotic cells were quantified. Study results indicated that soybean saponin treatment decreased cell growth in a concentration-dependent manner, and pre-treatment of the cells with saponins significantly suppressed the 12-O-tetradecanoyl phorbol 13-acetate-stimulated PKC activity. Cells treated with 300 and 600 ppm of saponins significantly increased alkaline phosphatase activity by 146% and 242% of the control, respectively. Also, 4-10 times more carcinoembryonic antigen was produced in cells treated with saponins. However, at all the concentrations used, saponins did not induce apoptosis, although there were slight decreases in apoptotic activity in cells treated with 240 and 600 ppm of soybean saponins. These results suggest that crude soybean saponin extract effectively suppresses PKC activation and induces differentiation, which possibly mediate the growth inhibition of tumor cells. Further experiments, including preclinical efficacy studies, are required to fully evaluate soybean saponins for their chemopreventive properties.
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PMID:Soybean saponins inhibit cell proliferation by suppressing PKC activation and induce differentiation of HT-29 human colon adenocarcinoma cells. 1158 95

Tributyrin (glyceryl tributyrate, TB) is known to induce malignant cells to differentiate followed by arrest of cell growth and death via apoptosis. We investigated the effects of TB on the distribution of cell cycle phases, differentiation as measured by alkaline phosphatase activity (ALP), and apoptosis of LS 174T colon cancer cells expressed by morphological changes, externalization of phosphatidylserine and stimulation of various caspases. TB (0.6 mM) reduced the proliferation by a 5-fold decrease of tumor cells in the S-phase and 1.3-fold increase in the G2/M-phase of cell cycle after 24 h of incubation. The ALP activity was enhanced in a dose-dependent manner up to 180-fold by 1 mM TB. Apoptosis was seen only above 0.6 mM TB (5-fold increase). Studies with caspase inhibitors revealed that TB mediated cell death was linked to up-regulation of caspases 3 and 8. Our results indicate that TB-induced differentiation promotes apoptosis in LS 174T cells and may explain the mode of action of TB finally resulting in an arrest of tumor cell growth.
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PMID:Tributyrin-induced differentiation promotes apoptosis of LS 174T colon cancer cells in vitro. 1174 64

Butyrate, a short-chain fatty acid produced in the colon by microbial fermentation of fiber, inhibits growth of colonic carcinoma cells while inducing differentiation. Resveratrol, a plant polyphenol found in red wine and peanuts, has been shown to exert chemopreventive properties on colon cancer cells. The aim of this study was to determine whether resveratrol modulates the effects of butyrate on Caco-2, a colonic adenocarcinoma cell line. The growth inhibitory effect of resveratrol (50 micromol/L) was more powerful than that of butyrate (2 mmol/L). Butyrate did not intensify the inhibition of proliferation exerted by resveratrol. Although the polyphenol enhanced the differentiation-inducing effect of butyrate, it did not elevate alkaline phosphatase activity or E-cadherin protein expression, markers of epithelial differentiation, when applied alone. Butyrate-induced transforming growth factor-beta1 secretion was inhibited by resveratrol. Treatment with the combination of resveratrol and butyrate attenuated levels of p27(Kip1), whereas resveratrol enhanced butyrate's effect on the induction of p21(Waf1/Cip1) expression. These data demonstrate a possible combined chemopreventive effect of two substances naturally occurring in the colonic lumen after ingestion of fibers and resveratrol-containing food.
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PMID:Resveratrol enhances the differentiation induced by butyrate in caco-2 colon cancer cells. 1209 97

One possible dietary factor that may increase susceptibility to colon cancer is inadequate copper intake. The objective of this study was to investigate the effects of low and adequate copper intakes on copper nutriture and putative risk factors for colon cancer susceptibility in healthy men. Seventeen healthy free-living nonsmoking men aged 21-52 y completed a 13-wk controlled feeding study in a randomized crossover design. The basal diet contained 0.59 mg Cu/13.65 MJ. After a 1-wk equilibration period in which the men consumed the basal diet supplemented with 1.0 mg Cu/d, they were randomly assigned to receive either the basal diet or the basal diet supplemented with 2 mg Cu/d for 6 wk. After the first dietary period, the men immediately began to consume the other level of Cu for the last 6 wk. They collected their feces during the equilibration period and during the last 2 wk of the two dietary periods for free radical and fecal water analysis. Low dietary copper significantly (P < 0.01) increased fecal free radical production and fecal water alkaline phosphatase activity. Low dietary copper significantly (P < 0.0001) decreased fecal water copper concentrations but did not affect fecal water volume, pH, iron or zinc concentrations. In contrast to the fecal analysis, hematological indicators of copper status were not significantly affected by the dietary treatments. These results suggest that low dietary copper adversely affects fecal free radical production and fecal water alkaline phosphatase activity, which are putative risk factors for colon cancer.
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PMID:Low dietary copper increases fecal free radical production, fecal water alkaline phosphatase activity and cytotoxicity in healthy men. 1256 94

Chlorophyllin (CHL), an antimutagenic and anticarcinogenic water-soluble derivative of chlorophyll, was recently found to be highly effective as a chemopreventive agent in a high-risk population exposed unavoidably to aflatoxin B(1) in the diet (P. A. Egner et al., Proc. Natl. Acad. Sci. USA, 98: 14601-14606, 2001). The current study examined the response of HCT116 human colon cancer cells to CHL treatment. Cells exposed to concentrations in the range 0.0625-0.5 mM CHL underwent growth arrest and apoptosis after 24 h, with the formation of a sub-G(1) peak in the attached cell population and nuclear condensation in the floating cell population. There was a concentration-dependent attenuation of mitochondrial membrane potential (deltapsi(m)) without the release of cytochrome c or activation of the caspase-9/caspase-3/poly(ADP-ribose) polymerase pathway. However, apoptosis-inducing factor was released from mitochondria into the cytosol and translocated to the nucleus, leading to concentration-dependent cleavage of nuclear lamins. The upstream mediators of this CHL-induced apoptosis pathway were identified as caspase-8/caspase-6 and truncated Bid, acting in conjunction with other proapoptotic members of the Bcl-2 family, such as Bak. These findings suggest that CHL might trigger apoptosis via interaction with putative "death receptors" in the plasma membrane of cancer cells, leading to initial cleavage of procaspase-8 and activation of subsequent downstream events, resulting in the destruction of nuclear lamins. Importantly, E-cadherin and alkaline phosphatase, which are indicators of cell differentiation, were strongly induced at all concentrations of CHL. Thus, in addition to being an effective blocking agent during the initiation phase, these findings support a role for CHL as a suppressing agent and as a possible novel therapeutic strategy directed toward aberrant cell proliferation in the colon.
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PMID:Caspase-8 and apoptosis-inducing factor mediate a cytochrome c-independent pathway of apoptosis in human colon cancer cells induced by the dietary phytochemical chlorophyllin. 1264 85

Butyrate and its prodrug tributyrin, as well as 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), have important physiological effects on proliferation and differentiation in a variety of malignant cells. The aim of this study was to elucidate the role of the vitamin D receptor (VDR) in butyrate-induced cell differentiation and cell cycle arrest in Caco-2 cells, a human colon cancer cell line. Cell differentiation was evaluated by analyzing the activity of alkaline phosphatase (AP). Protein of VDR, cyclins, cyclin-dependent kinases (cdks) and of cdk inhibitors was quantified by Western blot analysis, VDR-mRNA by PCR. Pre- and postconfluent cells were assessed for VDR binding activity. Cell cycle was analyzed by flow cytometry. Tributyrin significantly increased VDR-mRNA level (250% vs. control) and VDR binding activity. Butyrate also enhanced VDR protein content in the nucleus in a time- and dose-dependent manner and more potently than other short-chain fatty acids of a related structure. Both butyrate (640% vs. control) and 1,25-(OH)2D3 (350% vs. control) significantly stimulated differentiation, whereas combined treatment with butyrate and 1,25-(OH)2D3 resulted in a synergistic amplification of AP activity (1400% vs. control). In the presence of the VDR antagonist ZK 191732, butyrate-induced differentiation was completely abolished (150% vs. control). While butyrate alone increased p21Waf1/Cip1 expression and down-regulated cdk 6 and cyclin A, and combined exposure with 1,25-(OH)2D3 resulted in a synergistic enhancement of butyrate-induced changes, expressions did not change from control level after treatment with butyrate and ZK 191732. G1 cell cycle arrest induced by butyrate was also abolished after combined treatment with butyrate and ZK 191732. In conclusion, differentiation and cell cycle arrest of Caco-2 cells induced by butyrate are mediated by up-regulation of VDR, followed by a stimulation of the negative cell cycle regulator p21Waf1/Cip1 and by a down-regulation of cdk 6 and cyclin A, both involved in cell cycle progression.
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PMID:Short-chain fatty acids and colon cancer cells: the vitamin D receptor--butyrate connection. 1289 27

We report two cases of monostotic Paget's disease which were effectively treated with bisphosphonate. Case 1 was a 60-year-old female. Medical examination revealed high alkaline phosphatase (ALP) levels making her visit our clinic. Hematological examination showed high levels of ALP isozyme 3 and bone metabolism markers, and bone scintigraphy demonstrated strong accumulation of 99mTc on the skull. With the diagnosis of monostotic Paget's disease of the skull, treatment with bisphosphonate (etidronate) was started. The response to etidronate was good and after 12 weeks of treatment, the ALP levels decreased to about 26% of the levels before treatment, without the appearance of any symptoms or lesion development. One year and three months later, ALP increased again, and etidronate administration was resumed. However, four years after the diagnosis of the disease, etidronate became ineffective and oral administration of alendronate, a stronger bisphosphonate, was started at 5 mg/day. The patient responded favorably to the bisphosphonate and is still under observation. Case 2 was a 71-year-old female. High ALP levels were found during the follow-up of type 2 diabetes, and the case was diagnosed as monostotic Paget's disease of the pelvis based on bone metabolism markers and bone scintigraphy. Etidronate treatment at 200 mg/day resulted in the improvement of bone metabolism markers and bone scintigraphy findings. When she died of colon cancer twelve months later, with no marked progress of the Paget's disease of bone observed clinically.
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PMID:Two cases of monostotic Paget's disease: effects of bisphosphonate. 1459 11

Sphingomyelin (SM) metabolism in the gut has been implicated in colonic tumorigenesis. Intestinal alkaline sphingomyelinase (alk-SMase) hydrolyses SM in the intestinal content and at the brush border. The enzyme activity is decreased in the tissues of human colorectal tumours. This study examines whether site or chain-mutation of alk-SMase occurs in colon cancer HT-29 cells and Caco-2 cells. Total RNA was isolated and the cDNA of alk-SMase was amplified by RT-PCR. The size of the cDNA from HT-29 cells was smaller than that of the wild-type cDNA. DNA sequencing identified a deletion of exon 4 in alk-SMase cDNA in HT-29 cells. No mutation in genomic alk-SMase DNA from exon 3 to 5 was identified. The exon 4 deletion was caused by a shift of RNA splice site in chromosome 17q25. In Caco-2 cells, no mutation of alk-SMase cDNA was identified. Transient expression in COS-7 cells showed that the enzyme from the cDNA in HT-29 cells had little alk-SMase activity whereas that in Caco-2 cells was as active as the wild-type alk-SMase. The deleted region included residue His353, which is predicted to form a substrate-binding site of alk-SMase. H353A substitution resulted in a protein with no alk-SMase activity. In monolayer cultured Caco-2 cells and HT-29 cells the alk-SMase activities were low. However, to culture the cells under polarizing conditions increased alk-SMase activity and reduced SM level in Caco-2 cells. The alk-SMase activity varied in parallel with alkaline phosphatase activity. In conclusion, we identified an inactive deletion in alk-SMase in HT-29 cells, and a differentiation-related expression of the enzyme in Caco-2 cells. The results provide a molecular mechanism related to previous findings of reduced alk-SMase activity in human colon cancers.
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PMID:Identification of one exon deletion of intestinal alkaline sphingomyelinase in colon cancer HT-29 cells and a differentiation-related expression of the wild-type enzyme in Caco-2 cells. 1501 55

A high dietary intake of plant foods is thought to contribute to the prevention of colorectal cancers in humans and flavonoids as part of such a diet are considered to contribute to those protective effects. Quercetin is a major dietary flavonoid consumed with a diet rich in onions, tea, and apples. We used HT-29 human colon cancer cells and investigated the effects of quercetin on proliferation, apoptosis, and differentiation as processes shown to be disregulated during cancer development. To identify the cellular targets of quercetin action, two-dimensional gel electrophoresis was performed and proteins altered in expression level after quercetin exposure of cells were identified by mass spectrometry of peptide fragments generated by tryptic digestion. Quercetin inhibited the proliferation of HT-29 cells with an IC(50)-value of 81.2 +/- 6.6 microM. Cell differentiation based on surface expression of alkaline phosphatase was enhanced 4-fold and the activity of the pro-apoptotic effector caspase-3 increased 3-fold. Those effects were associated with the regulation of heat-shock proteins and annexins shown to both play a crucial role in the process of apoptosis. Cytoskeletal caspase substrates were found as regulated as well and various proteins involved in intermediary metabolism and in gene regulation showed altered steady-state expression levels upon quercetin treatment of cells. In conclusion, quercetin alters the levels of a variety of proteins involved in growth, differentiation, and apoptosis of colon cancer cells. Their identification as molecular targets of quercetin may explain the anti-cancer activities of this flavonoid.
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PMID:Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. 1522 76

Vitamin A and its metabolic forms, like all-trans retinoic acid (ATRA), are used with promising results in the treatment of many tumors. Two major problems in the clinical use of retinoids are that the doses needed for successful treatment are often toxic, leading to "hypervitaminosis A syndrome" and that patients often develop drug resistance. In order to find compounds that can overcome these problems, many new derivatives of retinoids have been synthesized and tested. Here we present a study on the effect of a new derivative of retinoic acid, IIF (pat. WIPO W0 00/17143), on growth and differentiation of two colon carcinomna cell lines, CaCo-2 and HT-29, with different degrees of tumorigenicity, the second one being more undifferentiated. The effect of IIF was compared with that of ATRA, whose antitumoral action on colon cancer cells and other tumoral cells is widely described in the literature. Besides exerting a strong antiproliferative effect, even higher than that of ATRA, IIF induced cellular differentiation, as demonstrated by the appearance of morphological (domes and microvilli formation) and biochemical (alkaline phosphatase induction) markers. Therefore, these findings indicate the new retinoid IIF as a possible candidate in the treatment of colon cancer.
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PMID:Retinoids and cancer: antitumor effect of ATRA and of a new derivative of retinoic acid, IIF, on colon carcinoma cell lines CaCo-2 and HT-29. 1527 55


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