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)

Screening of 26 gut peptides for their ability to inhibit growth of human colon cancer HT29-D4 cells grown in 10% fetal calf serum identified orexin-A and orexin-B as anti-growth factors. Upon addition of either orexin (1 microM), suppression of cell growth was total after 24 h and >70% after 48 or 72 h, with an EC(50) of 5 nm peptide. Orexins did not alter proliferation but promoted apoptosis as demonstrated by morphological changes in cell shape, DNA fragmentation, chromatin condensation, cytochrome c release into cytosol, and activation of caspase-3 and caspase-7. The serpentine G protein-coupled orexin receptor OX(1)R but not OX(2)R was expressed in HT29-D4 cells and mediated orexin-induced Ca(2+) transients in HT29-D4 cells. The expression of OX(1)R and the pro-apoptotic effects of orexins were also indicated in other colon cancer cell lines including Caco-2, SW480, and LoVo but, most interestingly, not in normal colonic epithelial cells. The role of OX(1)R in mediating apoptosis was further demonstrated by transfecting Chinese hamster ovary cells with OX(1)R cDNA, which conferred the ability of orexins to promote apoptosis. A neuroblastoma cell line SK-N-MC, which expresses OX(1)R, also underwent growth suppression and apoptosis upon treatment with orexins. Promotion of apoptosis appears to be an intrinsic property of OX(1)R regardless of the cell type where it is expressed. In conclusion, orexins, acting at native or recombinant OX(1)R, are pro-apoptotic peptides. These findings add a new dimension to the biological activities of these neuropeptides, which may have important implications in health and disease, in particular colon cancer.
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PMID:Orexins acting at native OX(1) receptor in colon cancer and neuroblastoma cells or at recombinant OX(1) receptor suppress cell growth by inducing apoptosis. 1531 Jul 63

It has been shown that excess stress to the endoplasmic reticulum (ER) triggers apoptosis, but the mechanisms underlying these processes remain unclear. We and others have reported previously that DR5 expression is up-regulated in thapsigargin (THG)-treated human cancer cells. Here, we provide evidence that CHOP is involved in THG up-regulation of DR5, which is a critical step for ER stress-induced apoptosis in human cancer cells. In human colon cancer HCT116 cells, knockdown of DR5 by siRNA blocked THG-induced Bax conformational change along with caspase-3 activation and cell death. Moreover, inhibition of CHOP expression attenuated DR5 up-regulation and apoptosis induced by THG, whereas ectopic expression of DR5 restored the sensitivity of CHOP siRNA-transfected cells to THG-induced apoptosis. In addition to HCT116 cells, inhibition of CHOP or DR5 induction also attenuated THG-induced cell death in other cancer cell lines including LNCaP, A2780S, and DU145, indicating that CHOP and DR5 are critical for ER stress-mediated apoptosis in human carcinoma cells. Furthermore, we identified a potential CHOP-binding site in the 5'-flanking region of the DR5 gene. Mutation of this site abrogated the enhanced reporter activity in response to THG treatment. Together, our findings suggest that CHOP regulates ER stress-induced apoptosis, at least in part, through enhancing DR5 expression in some types of human cancer cells.
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PMID:CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. 1532 75

Bilirubin is the principal end product of heme degradation. Prompted by epidemiologic analyses demonstrating an inverse correlation between serum bilirubin levels and cancer mortality, we examined the effect(s) of bilirubin on the growth and survival of colon adenocarcinoma cells. Adenocarcinoma cell monolayers were treated with bilirubin over a range of bilirubin:BSA molar ratios (0-0.6), and viability was assessed colorimetrically. Apoptosis was characterized by TUNEL assay, annexin V staining and caspase-3 activation. The mechanism(s) by which bilirubin induces apoptosis was investigated by Western blotting for cytochrome c release, assaying for caspase-8 and caspase-9 activation and for mitochondrial depolarization by JC-1 staining. The direct effect of bilirubin on the membrane potential of isolated mitochondria was evaluated using light-scattering and fluorescence techniques. Bilirubin decreased the viability of all colon cancer cell lines tested in a dose-dependent manner. Cells exhibited substantial apoptosis when exposed to bilirubin concentrations ranging 0-50 microM, as demonstrated by an 8- to 10-fold increase in TUNEL and annexin V staining and in caspase-3 activity. Bilirubin treatment evokes specific activation of caspase-9, enhances cytochrome c release into the cytoplasm and triggers the mitochondrial permeability transition in colon cancer monolayers. Additionally, bilirubin directly induces the depolarization of isolated rat liver mitochondria, an effect that is not inhibited by cyclosporin A. Bilirubin stimulates apoptosis of colon adenocarcinoma cells in vitro through activation of the mitochondrial pathway, apparently by directly dissipating mitochondrial membrane potential. As this effect is triggered at concentrations normally present in the intestinal lumen, we postulate a physiologic role for bilirubin in modulating colon tumorigenesis.
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PMID:Unconjugated bilirubin induces apoptosis in colon cancer cells by triggering mitochondrial depolarization. 1538 69

Effects of proanthocyanidin (PA), procyanidin B-2 (B-2), and epigallocatechin gallate (EGCG) on azoxymethane (AOM)-induced colonic preneoplastic aberrant crypt foci (ACF) formation were investigated using F344 rats. The numbers of total ACF in rats treated with 0.002% PA and 0.05% B-2 were significantly decreased compared with the AOM alone group (control). Cell proliferation in the colon, as shown by proliferating cells nuclear antigen (PCNA), was also reduced in those treatments. The single-stranded DNA (ssDNA) labeling index, a marker for apoptosis, was significantly increased in 0.002% PA and 0.05% B-2 groups compared with control. Moreover, the numbers of CD11b/c+ cells (macrophages) and NKR-P1A+ cells (NK cells) in the all groups were significantly increased compared with control. In an in vitro study using rat colon cancer cell line RCN-9, PA, especially 5-10mer of PA (PA5/10), strong growth inhibition was shown. PA5/10 caused the most remarkable apoptosis as cleared by FACS analysis. These cells showed significantly increased caspase-3 activity. The results would suggest that the PA, especially PA5/10, might strongly enhance caspase-3 activity and cause apoptosis in cancer cells. PA at fairly low doses in the long term might serve as an effective means for preventing colon carcinogenesis.
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PMID:Chemoprevention of colorectal cancer by grape seed proanthocyanidin is accompanied by a decrease in proliferation and increase in apoptosis. 1545 39

Ling Zhi extract (LZE) is a herbal mushroom preparation which been used world wide for the prevention and treatment of various cancers. The current study was designed to evaluate these claims in human colon cancer cells in terms of cancer preventive mechanisms. Results have demonstrated induction of apoptosis, anti-inflammatory action and differential cytokine expression during induced inflammation in the human colonic carcinoma cell line, HT-29. LZE caused no cytotoxicity in HT-29 cells at doses less than 10,000 microg/ml. Increasing concentrations of LZE reduced prostaglandin E2 production, but increased nitric oxide production. LZE treatment induced apoptosis by increasing the activity of caspase-3. RT-PCR showed that LZE at a concentration of 5000 microg/ml decreased the expression of cyclooxygenase-2 mRNA. Among 42 cytokines tested by protein array in this study, supplementation of LZE at doses of 500 and 5000 microg/ml to HT-29 cells reduced the expression of interleukin-8, macrophage inflammatory protein 1-delta, vascular epithelial growth factor, and platelet-derived growth factor. These results suggest that LZE has pro-apoptotic and anti-inflammatory functions, as well as inhibitory effects on cytokine expression during early inflammation in colonic carcinoma cells, which may be of significance in the use of Chinese herbal alternative medicines for cancer prevention.
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PMID:Effects of Ganoderma lucidum on apoptotic and anti-inflammatory function in HT-29 human colonic carcinoma cells. 1547 80

Activation of protein kinase C delta (PKCdelta) is believed to be pro-apoptotic. PKCdelta is reported to be reduced in colon cancers. Using a colon cancer cell line, COLO 205, we have examined the roles of PKCdelta in apoptosis and of caspase-3 in the activation and inhibition of PKCdelta. PKCdelta activation with bistratene A and its inhibition with rottlerin induced apoptosis. Effects of PKC activators and inhibitors were additive, suggesting that PKCdelta down-regulation was responsible for the effects on apoptosis. Different apoptotic pathways induced PKCdelta cleavage, but the fragment produced was inactive in kinase assays. Caspase-3 inhibition did not block DNA fragmentation or PKCdelta proteolysis despite blocking intracellular caspase-3 activity. Calpain inhibition with calpeptin did not prevent TPA-induced PKCdelta cleavage. We conclude that in colonocytes, inhibition of PKCdelta is sufficient to lead to caspase-3-independent apoptosis. Caspase-3 does not cleave PKCdelta to an active form, nor does caspase-3 inhibition block apoptosis.
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PMID:Protein kinase C delta is not activated by caspase-3 and its inhibition is sufficient to induce apoptosis in the colon cancer line, COLO 205. 1549 16

The platinum compound oxaliplatin has been shown to be an effective chemotherapeutic agent for the treatment of colorectal cancer. In this study, we investigate the molecular mechanisms of action of oxaliplatin to identify means of predicting response to this agent. Exposure of colon cancer cells to oxaliplatin resulted in G2/M arrest and apoptosis. Immunofluorescent staining demonstrated that the apoptotic cascade initiated by oxaliplatin is characterised by translocation of Bax to the mitochondria and cytochrome c release into the cytosol. Oxaliplatin treatment resulted in caspase 3 activation and oxaliplatin-induced apoptosis was abrogated by inhibition of caspase activity with z-VAD-fmk, but was independent of Fas/FasL association. Targeted inactivation of Bax or p53 in HCT116 cells resulted in significantly increased resistance to oxaliplatin. However, the mutational status of p53 was unable to predict response to oxaliplatin in a panel of 30 different colorectal cancer cell lines. In contrast, the expression profile of these 30 cell lines, assessed using a 9216-sequence cDNA microarray, successfully predicted the apoptotic response to oxaliplatin. A leave-one-out cross-validation approach was used to demonstrate a significant correlation between experimentally observed and expression profile predicted apoptosis in response to clinically achievable doses of oxaliplatin (R=0.53; P=0.002). In addition, these microarray experiments identified several genes involved in control of apoptosis and DNA damage repair that were significantly correlated with response to oxaliplatin.
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PMID:Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells. 1554 75

Plant sterols are found in fruits and vegetables. Their cholesterol-lowering effect is well documented. Our study aimed at comparing antiproliferative effects of 7beta-hydroxysitosterol (7beta-OHsito) versus 7beta-hydroxycholesterol (7beta-OHchol) on the human colon cancer cell line Caco-2. When cells were exposed for 32 h to 60 microM 7beta-OHsito or to 30 microM 7beta-OHchol, both compounds caused 50% growth inhibition. Cells treated with 7beta-OHsito showed enhanced caspase-9 and -3 activities followed by DNA fragmentation. In contrast, 7beta-OHchol did not activate caspase-3 and activation of caspase-9 and DNA fragmentation were delayed. The treatment of cells with the caspase inhibitor Z-VAD.fmk retarded the 7beta-OHsito-induced apoptotic process but not that triggered by 7beta-OHchol. Our data suggest that the two compounds in spite of their structural similarities target different cellular pathways, which lead to cell death.
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PMID:Different apoptotic mechanisms are involved in the antiproliferative effects of 7beta-hydroxysitosterol and 7beta-hydroxycholesterol in human colon cancer cells. 1555 Sep 35

1, 6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl]diamantine (DPD), a new cytostatic and differentiation inducing agent, was found to inhibit the growth of several cancer cell lines in the National Cancer Institute (NCI) Anticancer Drug Screen system. Previously, we demonstrated that DPD inhibited the growth of human colon cancer cell lines both in vitro and in vivo. In this study, we examined the anticancer effects of DPD on two human leukemia cells lines. DPD exerted growth inhibitory activities in vitro against two human leukemia cell lines, the promyeloid line HL-60 and the lymphoblastic line Molt-3. The in vivo effect of tumor growth suppression by DPD was also observed in mouse xenografts. No acute toxicity was observed after an intra-peritoneal challenge of DPD in "severe combined immune-deficiency" (SCID) mice twice a week. The in vitro study showed HL-60 was more sensitive to DPD than Molt-3 through induction of G(0)/G(1) cell-cycle arrest with the appearance of a hypodiploid DNA fraction. The increased superoxide (O(2)(-)), dissipation of the mitochondrial membrane potential, activation of caspase 3, and increase in annexin V binding were evident before apoptosis in DPD-treated cells. The superoxide dismutase 1 (SOD1) mRNA expression was also decreased in DPD-treated HL-60 and Molt-3 cells. Thus, it appeared that inhibition of SOD might be the major cause for the production of cellular superoxide with concomitant decrease of H(2)O(2) in DPD-treated cells. Addition of antioxidant can reduce DPD-induced mitochondrial damage, caspase activation, and annexin V binding in HL-60 cells. The results suggest that the cellular generation of O(2)(-) plays a role in initiating and coordinating DPD-mediated growth arrest and apoptosis of HL-60 cells. Importantly, addition of arsenic trioxide, a compound capable of reactive oxygen species (ROS) generation, significantly enhanced the in vitro activity of DPD. These results suggest that DPD appears to be a potential new modality in human leukemia therapy.
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PMID:Effects of 1, 6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl]diamantane (DPD), a reactive oxygen species and apoptosis inducing agent, on human leukemia cells in vitro and in vivo. 1558 71

The p53 protein activates cellular death programs through multiple pathways. Because the high frequency of p53 mutations in human tumors is believed to contribute to resistance to commonly used chemotherapeutic agents, it is important to identify drugs that induce p53-independent cell death and to define the mechanisms of action of such drugs. Here we screened a drug library (the National Cancer Institute mechanistic set; 879 compounds with diverse mechanisms of actions) and identified 175 compounds that induced caspase cleavage of cytokeratin-18 in cultured HCT116 colon cancer cells at <5 microM. Interestingly, whereas most compounds elicited a stronger apoptotic response in cells with functional p53, significant apoptosis was observed also in p53-null cells. A subset of 15 compounds showing weak or no dependence on p53 for induction of apoptosis was examined in detail. Of these compounds, 11 were capable of activating caspase-3 in enucleated cells. Seven such compounds with nonnuclear targets were found to induce lysosomal membrane permeabilization (LMP). Translocation of the lysosomal proteases cathepsin B and cathepsin D into the cytosol was observed after treatment with these drugs, and apoptosis was inhibited by pepstatin A, an inhibitor of cathepsin D. Apoptosis depended on Bax, suggesting that LMP induced a mitochondrial apoptotic pathway. We conclude that a large number of potential anticancer drugs induce p53-independent apoptosis and that LMP is a mediator of many such responses.
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PMID:Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis. 1561 92


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