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)

Astragalus membranaceus has been used to ameliorate the side effects of anti-neoplastic drugs. We recently reported that total Astragalus saponins (AST) possess anti-tumor properties in human colon cancer cells and tumor xenografts. Nevertheless, the precise mechanism of action has not been fully elucidated. The present study aimed to unveil the anti-carcinogenic potential of AST in HepG2 human hepatocellular carcinoma (HCC) cells and to clarify the signaling pathway. We demonstrated here that AST downregulated expression of the HCC tumor marker alpha-fetoprotein and suppressed HepG2 cell growth by inducing apoptosis. AST also caused caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage, nuclear chromatin condensation, with downregulation of the anti-apoptotic proteins bcl-2 and bcl-xL and decreased nuclear factor-kappa B (NF-kappaB)/DNA-binding activity. Concomitantly, expression of the phosphorylated form of the extracellular signal-regulated protein kinase (ERK) was prominently increased. Nevertheless, pretreatment of ERK inhibitor PD98059 did not attenuate AST-induced PARP cleavage. Taken together, these results exemplify that AST induced growth inhibition and promoted apoptosis in HepG2 cells through modulation of an ERK-independent NF-kappaB signaling pathway.
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PMID:Astragalus saponins induce apoptosis via an ERK-independent NF-kappaB signaling pathway in the human hepatocellular HepG2 cell line. 1914 42

Despite the availability of several Food and Drug Administration-approved drugs, advanced inoperable colorectal cancer remains incurable. In this study, we focused on the development of combined molecular targeted therapies against colon cancer by testing the efficacy of the combination of the histone deacetylase inhibitor vorinostat with the proteasome inhibitor bortezomib to determine if this resulted in synergistic antitumor effects against colorectal cancer. The effects of the histone deacetylase inhibitor vorinostat in combination with the proteasome inhibitor bortezomib on the growth of two colorectal cancer cell lines were assessed with regard to proliferation, cell cycle arrest, and apoptosis. Treatment with the combination of vorinostat and bortezomib resulted in a synergistic decrease in proliferation of both colorectal cancer cell lines compared with treatment with single agents alone. This inhibition was associated with a synergistic increase in apoptosis as measured by caspase-3/7 activity and cleaved poly(ADP-ribose) polymerase. In addition, we observed an increase in the proapoptotic protein BIM and in the number of cells arrested in the G(2)-M phase of the cell cycle. Although p21 levels were significantly increased, short hairpin RNA knockdown of p21 did not lead to changes in proliferation in response to the combination of drugs, indicating that although p21 is a target of these drugs, it is not required to mediate their antiproliferative effects. These data indicate that combination treatment with vorinostat and bortezomib result in synergistic antiproliferative and proapoptotic effects against colon cancer cell lines, providing a rational basis for the clinical use of this combination for the treatment of colorectal cancer.
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PMID:Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models. 1917 60

We observed that treatment of prostate cancer cells for 24 h with magnolol, a phenolic component extracted from the root and stem bark of the oriental herb Magnolia officinalis, induced apoptotic cell death in a dose- and time-dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in magnolol-treated cells. Treatment of PC-3 cells with an apoptosis-inducing concentration of magnolol (60 microM) resulted in a rapid decrease in the level of phosphorylated Akt leading to inhibition of its kinase activity. Magnolol treatment (60 microM) also caused a decrease in Ser((136)) phosphorylation of Bad (a proapoptotic protein), which is a downstream target of Akt. Protein interaction assay revealed that Bcl-xL, an anti-apoptotic protein, was associated with Bad during treatment with magnolol. We also observed that during treatment with magnolol, translocation of Bax to the mitochondrial membrane occurred and the translocation was accompanied by cytochrome c release, and cleavage of procaspase-8, -9, -3, and poly(ADP-ribose) polymerase (PARP). Similar results were observed in human colon cancer HCT116Bax(+/-) cell line, but not HCT116Bax(-/-) cell line. Interestingly, at similar concentrations (60 microM), magnolol treatment did not affect the viability of normal human prostate epithelial cell (PrEC) line. We also observed that apoptotic cell death by magnolol was associated with significant inhibition of pEGFR, pPI3K, and pAkt. These results suggest that one of the mechanisms of the apoptotic activity of magnolol involves its effect on epidermal growth factor receptor (EGFR)-mediated signaling transduction pathways.
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PMID:Magnolol induces apoptosis via inhibiting the EGFR/PI3K/Akt signaling pathway in human prostate cancer cells. 1922 60

The relationship between sphingosine kinase (SPHK), cellular ceramide concentration and chemosensitivity was investigated in human colon cancer cell lines. Among nine colon cancer cell lines, SPHK1 and SPHK2 activity and protein expression was highest in RKO cells and lowest in HCT116 cells. A viability assay revealed that HCT116 cells were sensitive to the effects of oxaliplatin (l-OHP), whereas RKO cells were resistant to those of l-OHP. Treatment with 5microg/ml l-OHP induced a marked time-dependent increase in various ceramides (C16, C24, C24:1) in HCT116 cells but not in RKO cells, as indicated by liquid chromatography/mass spectrometry. The increase in ceramide and caspase activation induced by l-OHP in the sensitive HCT116 cells was abolished by pretreatment with a neutral sphingomyelinase inhibitor, suggesting that the ceramide formation was due to the activation of neutral, rather than acid, sphingomyelinase. In contrast, in l-OHP-resistant RKO cells, treatment with an SPHK inhibitor or SPHK1 and SPHK2 silencing by RNA interference suppressed cell viability and increased caspase activity and cellular ceramide formation after l-OHP treatment. The elevated ceramide formation induced by SPHK inhibition and l-OHP was inhibited by fumonisin B1 but not myriocin, suggesting that ceramide formation was through the salvage pathway. Endogenous phosphorylated Akt levels were much higher in the resistant RKO cells than in the sensitive HCT116 cells. Either SPHK1 or SPHK2 silencing in RKO cells decreased phosphorylated Akt levels and increased p53 and p21 protein levels as well as poly(ADP-ribose) polymerase cleavage in response to l-OHP treatment. These findings indicate that SPHK isoforms and neutral sphingomyelinase contribute to the regulation of chemosensitivity by controlling ceramide formation and the downstream Akt pathway in human colon cancer cells.
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PMID:Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and Akt activation. 1924 26

Epidemiological evidence suggests that the intake of prebiotic dietary fibres, for example, inulin, protects against colorectal cancer. However, little is known about cellular responses to complex fermentation samples. Therefore, we prepared a fermentation supernatant fraction of inulin and studied biological properties in human colon cell lines, LT97 and HT29 (representing early and late stages of colon cancer). Inulin enriched with oligofructose (Synergy 1) was incubated under anaerobic conditions with faecal inocula and the supernatant fraction was characterised for content of SCFA and secondary bile acid deoxycholic acid (DCA). A Synergy fermentation supernatant fraction (SFS) and a synthetic fermentation mixture (SFM) mimicking the SFS in SCFA and DCA content were used in the concentration range of 1.25-20 % (v/v) for 24-72 h. The effects on cell growth were determined by quantifying DNA. Effects on apoptosis were analysed by measuring poly(ADP-ribose) polymerase (PARP) cleavage using Western blotting. Compared with the faecal blank, produced without the addition of inulin, the SFS resulted in an almost 2.5-fold increase of SCFA and 3.4-fold decrease of DCA. In comparison with HT29 cells, LT97 cells responded more sensitively to the growth-inhibitory activities. Additionally, a significant increase in PARP cleavage was observed in LT97 cells after incubation with the SFS, demonstrating induction of apoptosis. The present results indicate growth-inhibiting and apoptosis-inducing effects of fermentation supernatant fractions of inulin. Moreover, since early adenoma cells were found to be more sensitive, this may have important implications for chemoprevention when translated to the in vivo situation, because survival of early transformed cells could be reduced.
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PMID:Fermentation products of inulin-type fructans reduce proliferation and induce apoptosis in human colon tumour cells of different stages of carcinogenesis. 1925 May 71

Fisetin, or 3,3',4',7-tetrahydroxyflavone, is present in fruits and vegetables and has been previously reported to inhibit the proliferation of a variety of cancer cells (Lu X, Jung J, Cho HJ, Lim do Y, Lee HS, Chun HS, Kwon DY, Park JH. J Nutr 135: 2884-2890, 2005). We have demonstrated in a previous work that 20-60 micromol/l fisetin inhibits cyclin-dependent kinase activities resulting in cell cycle arrest in HT-29 colon cancer cells. In the present study, we attempted to characterize the mechanisms by which fisetin induces apoptosis in HCT-116 cells. DNA condensations, cleavage of poly(ADP-ribose) polymerase (PARP), and cleavage of caspases 9, 7, and 3 were induced in HCT-116 cells treated with 5-20 micromol/l of fisetin. Fisetin induced a reduction in the protein levels of antiapoptotic Bcl-xL and Bcl-2 and an increase in the levels of proapoptotic Bak and Bim. Fisetin did not affect the Bax protein levels, but induced the mitochondrial translocation of this protein. Fisetin also enhanced the permeability of the mitochondrial membrane and induced the release of cytochrome c and Smac/Diablo. Additionally, fisetin caused an increase in the protein levels of cleaved caspase-8, Fas ligand, death receptor 5, and TNF-related apoptosis-inducing ligand, and the caspase-8 inhibitor Z-IETD-FMK suppressed fisetin-induced apoptosis and the activation of caspase-3. Furthermore, fisetin increases p53 protein levels, and the inhibition of p53 expression by small interference RNA resulted in a decrease in the fisetin-induced translocation of Bax to the mitochondria, release of mono- and oligonucleosome in the cytoplasm, and PARP cleavage. These results show that fisetin induces apoptosis in HCT-116 cells via the activation of the death receptor- and mitochondrial-dependent pathway and subsequent activation of the caspase cascade. The induction of p53 results in the translocation of Bax to the mitochondria, which contributes to fisetin-induced apoptosis in HCT-116 cells.
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PMID:Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin. 1926 55

Oxidative/nitrosative stress and generation of proinflammatory cytokines are hallmarks of inflammation. Because chronic inflammation is implicated in several pathologic conditions in humans, including cancers of the colon, anti-inflammatory compounds may be useful chemopreventive agents against colon cancer. Stilbenes, such as resveratrol, have diverse pharmacologic activities, which include anti-inflammation, cancer prevention, a cholesterol-lowering effect, enhanced insulin sensitivity, and increased life span. We previously showed that pterostilbene (trans-3,5-dimethoxy-4'-hydroxystilbene), a structural analogue of resveratrol, is present in blueberries and that pterostilbene inhibited expression of certain inflammation-related genes in the colon and suppressed aberrant crypt foci formation in rats. Here, we examined molecular mechanisms of the action of pterostilbene in colon cancer. Pterostilbene reduced cell proliferation, down-regulated the expression of c-Myc and cyclin D1, and increased the level of cleaved poly(ADP-ribose) polymerase. A combination of cytokines (tumor necrosis factor-alpha, IFN-gamma, and bacterial endotoxin lipopolysaccharide) induced inflammation-related genes such as inducible nitric oxide synthase and cyclooxygenase-2, which was significantly suppressed by treatment with pterostilbene. We further identified upstream signaling pathways contributing to the anti-inflammatory activity of pterostilbene by investigating multiple signaling pathways, including nuclear factor-kappaB, Janus-activated kinase-signal transducer and activator of transcription, extracellular signal-regulated kinase, p38, c-Jun NH(2)-terminal kinase, and phosphatidylinositol 3-kinase. Cytokine induction of the p38-activating transcription factor 2 pathway was markedly inhibited by pterostilbene among the different mediators of signaling evaluated. By silencing the expression of the p38 alpha isoform, there was significant reduction in cytokine induction of inducible nitric oxide synthase and cyclooxygenase-2. Our data suggest that the p38 mitogen-activated protein kinase cascade is a key signal transduction pathway for eliciting the anti-inflammatory action of pterostilbene in cultured HT-29 colon cancer cells.
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PMID:Anti-inflammatory action of pterostilbene is mediated through the p38 mitogen-activated protein kinase pathway in colon cancer cells. 1954 98

Cancer is one of the leading causes of death in the world. The triterpenoid compound asiatic acid derived from the tropical medicinal plant Centella asiatica displays cytotoxic activity on fibroblast cells and several other kinds of cells. The present work studies asiatic acid-mediated growth inhibition of cancer cells and the underlying mechanism. Asiatic acid markedly inhibited cancer cell proliferation. Apoptosis of SW480 human colon cancer cells was induced by asiatic acid as shown by flow cytometry, DNA fragmentation and nuclear chromatin condensation experiments. Through increasing mitochondrial membrane permeability and cytochrome c release from mitochondria into cytosol, asiatic acid induced caspase-9 activity, which further activated caspase-3 and poly(ADP-ribose) polymerase cleavage resulting in irreversible apoptotic death in the tumor cells. Taken together, these results suggest that mitochondrial death apoptosis cascade plays very important roles in asiatic acid-induced cancer apoptosis.
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PMID:Asiatic acid induces colon cancer cell growth inhibition and apoptosis through mitochondrial death cascade. 1965 80

This study investigated the apoptotic regulation by green tea catechin epigallcatechin-3-gallate (EGCG) on colon cancer cells in the presence of low-dose H(2)O(2) known to exert the activation of signal pathways leading to cell proliferation. In the presence of low-dose H(2)O(2), EGCG induced apoptosis and abolished the cell-proliferative effect exhibited by low-dose H(2)O(2). This reduction of growth was accompanied by an activation of AMP-activated kinase (AMPK), a decrease in cyclooxygenase-2 (COX-2) expression and prostaglandin E(2) (PGE(2)) levels, and the induction of apoptotic markers such as p53 and poly(ADP-ribose) polymerase (PARP) cleavage. The low-dose H(2)O(2) stimulated COX-2 expression, and treating cells with synthetic AMPK activator AICAR (5-aminoimiazole-4-carboxamide-1-beta-d-ribofuranoside) resulted in greater suppression of COX-2 expression and PGE(2). By treating cells with high concentrations of the reactive oxygen species (ROS) scavenger NAC (N-acetyl-1-cysteine), the apoptotic effect of EGCG was abolished and led to suppression of AMPK and COX-2, indicating that the liberation of excessive ROS might be the upstream signal of the AMPK-COX-2 signaling pathway even in the presence of low-dose H(2)O(2).
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PMID:Green tea catechin controls apoptosis in colon cancer cells by attenuation of H2O2-stimulated COX-2 expression via the AMPK signaling pathway at low-dose H2O2. 1972 1

The antitumor activity of fucoidan from Fucus vesiculosus was investigated in human colon carcinoma cells. The crude fucoidan, a polysaccharide composed predominantly of sulfated fucose, markedly inhibited the growth of HCT-15 cells (human colon carcinoma cells). After HCT-15 cells were treated with fucoidan, several apoptotic events such as DNA fragmentation, chromatin condensation and increase of the population of sub-G1 hypodiploid cells were observed. In the mechanism of fucoidan-induced apoptosis, we examined changes in Bcl-2 and Bax protein expression levels and activation of caspases. Fucoidan decreased Bcl-2 expression, whereas the expression of Bax was increased in a time-dependent manner compared to the control. In addition, the active forms of caspase-9 and caspase-3 were increased, and the cleavage of poly(ADP-ribose) polymerase (PARP), a vital substrate of effector caspase, was observed. Furthermore, the induction of apoptosis was also accompanied by a strong activation of extracellular signal-regulated kinase (ERK) and p38 kinase and an inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt in a time-dependent manner. These findings provide evidence demonstrating that the pro-apoptotic effect of fucoidan is mediated through the activation of ERK, p38 and the blocking of the PI3K/Akt signal pathway in HCT-15 cells. These data support the hypothesis that fucoidan may have potential in colon cancer treatment.
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PMID:Apoptosis inducing activity of fucoidan in HCT-15 colon carcinoma cells. 1980 40


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