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)

Hyperplasia suppressor gene (HSG), also called human mitofusin 2, is a novel gene that markedly suppresses the cell proliferation of hyperproliferative vascular smooth muscle cells from spontaneously hypertensive rat arteries. This gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. In this report, we showed that an adenovirus vector encoding human HSG (Ad5-hHSG) had an antitumor activity in a wide range of cancer cell lines. We further focused on the lung cancer cell line A549 and the colon cancer cell line HT-29 and then observed that Ad5-hHSG induced apoptosis both in vitro and in vivo. Confocal laser scanning microscopy and electron microscopy revealed that cells infected with Ad5-hHSG formed dose-dependent perinuclear clusters of fused mitochondria. Adenovirus-mediated hHSG overexpression induced apoptosis, cell cycle arrest, mitochondrial membrane potential (DeltaPsim) reduction and release of cytochrome c, caspase-3 activation, and cleavage of PARP in vitro. Overexpression of hHSG also significantly suppressed the growth of subcutaneous tumors in nude mice both ex vivo and in vivo. In addition, Ad5-hHSG increased the sensitivity of these cell lines to two chemotherapeutic agents, VP16 and CHX, and radiation. These results suggest that Ad5-hHSG may serve as an effective therapeutic drug against tumors.
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PMID:Adenovirus-expressed human hyperplasia suppressor gene induces apoptosis in cancer cells. 1820 24

The aim of this study was to investigate the effect of quercetin, a flavonoid, on the apoptotic pathway in a human prostate cell line (LNCaP). We observed that treatment of cells for 24h with quercetin-induced cell death in a dose-dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in quercetin-treated cells. Treatment of LNCaP cells with an apoptosis inducing concentration of quercetin (100 microM) resulted in a rapid decrease in the inhibitory Ser473 phosphorylation of Akt leading to inhibition of its kinase activity. Quercetin treatment (100 microM) also caused a decrease in Ser136 phosphorylation of Bad, which is a downstream target of Akt. Protein interaction assay revealed that during treatment with quercetin, Bcl-xL dissociated from Bax and then associated with Bad. Our results also show that quercetin decreases the Bcl-xL:Bax ratio and increases translocation and multimerization of Bax to the mitochondrial membrane. The translocation is accompanied by cytochrome c release, and procaspases-3, -8 and -9 cleavage and increased poly(ADP-ribose) polymerase (PARP) cleavage. Similar results were observed in human colon cancer HCT116Bax+/+ cell line, but not HCT116Bax-/- cell line. Interestingly, at similar concentrations (100 microM), quercetin treatment did not affect the viability or rate of apoptosis in normal human prostate epithelial cell line (PrEC) and rat prostate epithelial cell line (YPEN-1). Our results indicate that the apoptotic processes caused by quercetin are mediated by the dissociation of Bax from Bcl-xL and the activation of caspase families in human prostate cancer cells.
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PMID:Role of Bax in quercetin-induced apoptosis in human prostate cancer cells. 1845 2

1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes (C-DIMs) activate the orphan receptors peroxisome proliferator-activated receptor gamma (PPARgamma) and Nur77 and induce receptor-dependent and -independent apoptotic pathways in colon and other cancer cells. Structure-activity studies show that the p-bromo (DIM-C-pPhBr) and p-fluoro (DIM-C-pPhF) analogs, which exhibit minimal activation of Nur77 and PPARgamma, induce expression of CCAAT/enhancer-binding protein homologous protein (CHOP/GADD153) in colon cancer cells. Moreover, among a series of bromo and fluoro C-DIM analogs, their induction of CHOP was dependent on the position of the phenyl substituents (para >/= meta >/= ortho) and required a free indole group. DIM-C-pPhBr and DIM-C-pPhF not only induced CHOP but also activated death receptor 5 (CHOP dependent), cleavage of caspase 8 and poly (ADP ribose) polymerase (PARP) that is consistent with activation of the extrinsic pathway of apoptosis. These responses were associated with the activation of c-jun N-terminal kinase (JNK) pathway since inhibition of JNK inhibited induction of the extrinsic apoptotic pathway by these C-DIMs. However, in contrast to classical inducers of endoplasmic reticulum (ER) stress such as tunicamycin and thapsigargin, the C-DIM compounds did not induce glucose-related protein 78 that is a marker of ER stress. Proapoptotic and anticarcinogenic effects were also observed in athymic nude mice bearing RKO cell xenografts and treated with 30 mg/kg/day DIM-C-pPhBr and this was accompanied by increased JNK phosphorylation in the tumors. Thus, the anticarcinogenic activity of DIM-C-pPhBr in colon cancer cells and tumors is related to a novel ER stress-independent activation of JNK.
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PMID:1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through activation of c-jun N-terminal kinase. 1846 Apr 48

We investigated whether the anticancer effect of a combination of XIAP down-regulation and PPAR gamma activation on colon cancer is PPARgamma receptor dependent. HCT116-XIAP(+/+) cells and HCT116-XIAP(-/-) cells were treated with troglitazone or 15-deoxy-Delta(12,14)-prostaglandin J2 (15-PGJ2) with or without prior exposure to PPARgamma inhibitor GW9662. Cell proliferation and apoptosis was evaluated. Athymic mice carrying HCT116-XIAP(-/-) cells-derived tumors were treated with troglitazone in the presence or absence of GW9662. Inhibition of cell proliferation and induction of apoptosis by troglitazone and 15-PGJ2 were more prominent in HCT116-XIAP(-/-) cells. PPARgamma ligand-induced growth inhibition, apoptosis, caspase and PARP cleavage could not be blocked by GW9662. Troglitazone significantly retarded growth of xenograft tumors and this effect was not blocked by GW9662. Marked apoptosis and an up-regulation of E-cadherin were observed in xenograft tumor tissues, and GW9662 did not affect these effects. Thus, a combination of XIAP down-regulation and PPARgamma ligands exert a significant anticancer effect in colon cancer via a PPARgamma independent pathway.
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PMID:Loss of XIAP sensitizes colon cancer cells to PPARgamma independent antitumor effects of troglitazone and 15-PGJ2. 1847 1

Farnesol (FOH) and geranylgeraniol (GGOH) possess anti-tumor potential, while peroxisome proliferator-activated receptor gamma (PPARgamma) has exhibited modulating effects in colorectal cancers. We investigated the anti-carcinogenic effects of these isoprenols in HT-29 and HCT116 colon cancer cells and PPARgamma involvement. Results indicate that the FOH- and GGOH-induced apoptosis involve caspase 3 activation, PARP cleavage, nuclear chromatin condensation, down-regulation of Bcl-x(L) and survivin expression, with increased PPARgamma promoter activity. Pretreatment of the PPARgamma antagonist GW9662 reduces FOH-induced growth inhibition and the associated PARP cleavage. We conclude that PPARgamma activation is essential to elicit the anti-carcinogenic action of herbal isoprenols in colonic cancer cells.
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PMID:Herbal isoprenols induce apoptosis in human colon cancer cells through transcriptional activation of PPARgamma. 1860 13

Because of unsatisfactory treatment options for colon cancer, there is a need to develop novel preventive approaches for this malignancy. One such strategy is through chemoprevention by the use of non-toxic dietary substances and botanical products. Delphinidin, an anthocyanidin in pigmented fruits and vegetables, possesses strong anti-oxidant and anti-inflammatory properties. In the present study, we investigated the antiproliferative and proapoptotic properties of delphinidin in human colon cancer HCT116 cells. We found that treatment of cells with delphinidin (30-240 microM; 48 h) resulted in (i) decrease in cell viability (ii) induction of apoptosis, (iii) cleavage of PARP, (iv) activation of caspases-3, -8, and -9, (v) increase in Bax with a concomitant decrease in Bcl-2 protein, and (vi) G2/M phase cell cycle arrest. NF-kappaB provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of both pre-neoplastic and malignant cells to resist apoptosis-based tumor surveillance mechanisms. We therefore, determined the effect of delphinidin on NF-kappaB signaling pathway. The immunoblot, ELISA and EMSA analysis demonstrated that the treatment of HCT116 cells with delphinidin resulted in the inhibition of (i) IKKalpha, (ii) phosphorylation and degradation of IkappaBalpha, (iii) phosphorylation of NF-kappaB/p65 at Ser(536), (iv) nuclear translocation of NF-kappaB/p65, (v) NF-kappaB/p65 DNA binding activity, and (vi) transcriptional activation of NF-kappaB. Our results suggest that delphinidin treatment of HCT116 cells suppressed NF-kappaB pathway, resulting in G2/M phase arrest and apoptosis. We suggest that delphinidin could have potential in inhibiting colon cancer growth.
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PMID:Delphinidin, an anthocyanidin in pigmented fruits and vegetables, induces apoptosis and cell cycle arrest in human colon cancer HCT116 cells. 1872 3

In our previous study we have proved that colon cancer cells HT-29 pre-treated with specific 5-lipoxygenase inhibitor MK-886 became more susceptible to photodynamic therapy (PDT) with hypericin and we also found that this mutual combination induced cell cycle arrest and stimulated onset of apoptosis (Kleban et al., 2007. J. Photochem. Photobiol. B 84, 2). To further explain events associated with MK-886 mediated sensitization of tumor cells toward PDT with hypericin, more detailed study of signaling pathways leading to increase in apoptosis as well as cell cycle perturbations was performed and is presented herein. Intensive accumulation of HT-29 cells in G0/G1 phase of cell cycle led to expression analyses of several G0/G1 checkpoint molecules (cyclin A, cyclin E, cdk-2, pRb). Similarly, accumulation of apoptotic cells invoked analyses of key molecules involved in apoptotic signaling (caspase-3, -8, -9; PARP; Lamin B; Mcl-1; Bax) by Western blotting and caspase activity assay. Long term survival of cells was examined by clonogenicity test. As the effect of PDT is mediated by ROS production, levels of hydrogen peroxides and superoxide anion were monitored by flow cytometric analyses. In addition, an impact of MK-886 on LTB4 production and expression of 5-LOX was monitored. Massive G0/G1 arrest in the cell cycle accompanied by increase in cyclin E level and decrease/absention of cyclin A, cdk-2 and pRb expression indicated incapability for G1/S transition. Minimal changes in cleavage of procaspases observed in cells treated with non-toxic concentrations of either agent alone or their mutual combination were not quite in line with their activity (caspase-3, -8, -9) which was significantly increased mainly in combinations. Treatment with non-toxic concentration of MK-886 had minimal influence over ROS production compared to control cells. In contrast, hypericin alone markedly increased the level of ROS, but no additional effect of MK-886 pre-treatment was detected. Further analyses of particular ROS groups unveiled an impact of increasing MK-886 concentration on superoxide accumulation accompanied with depletion of hydrogen peroxide level within the cells. The clonogenicity test revealed disruption of colony formation after mutual combination of both agents as compared to MK-886 or PDT alone. In conclusion, we presume that stimulation of apoptosis in our experimental model was accomplished preferentially through the mitochondrial pathway, although caspase-8 activation was also noticed. Interestingly, pre-treatment with MK-886 modulated distribution of ROS production in mutual combination with PDT.
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PMID:Mechanisms involved in the cell cycle and apoptosis of HT-29 cells pre-treated with MK-886 prior to photodynamic therapy with hypericin. 1877 33

There is epidemiological evidence, that mesalazine can inhibit colon cancer development by affecting proliferation and apoptosis. Several studies suggest that supplementary intake of butyrate may yield to improved efficacy of mesalazine. However, the underlying molecular mechanisms of such interaction remain unknown. This study addressed the combinatory effect of both substances on the growth of Caco-2 cells. Challenging of cells with mesalazine and butyrate provoked a time-dependent decrease in both cell counts and proliferation. Co-treatment with the substances could further intensify these effects. The growth-inhibitory action of mesalazine and butyrate was accompanied by a significant increase in caspase-3 activity, cleavage of PARP and caspase-8, while decreasing the expression of Xiap and Survivin simultaneously. Co-incubation of both substances exaggerated effects on all examined apoptosis-regulatory proteins except for Xiap. Our data demonstrate that co-treatment of mesalazine and butyrate evoked additive effects on inhibition of cell growth and induction of apoptosis in Caco-2 cells.
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PMID:Combined treatment of Caco-2 cells with butyrate and mesalazine inhibits cell proliferation and reduces Survivin protein level. 1877 38

Lebanese sage essential oil possesses antitumor properties, however, the bioactive components and antitumor mechanisms are not known. Here we show that combining the three sage bioactive compounds, Linalyl acetate (Ly), Terpeniol (Te) and Camphor (Ca), caused synergistic inhibition of the growth of two isogenic human colon cancer cell lines HCT-116 (p53(+/+) and p53(-/-)) and had no effect on growth of FHs74Int normal human intestinal cell line. In p53(+/+) cells, the combination of Ly + Te + Ca (10(-3) M of each) caused significant accumulation of cells in PreG(1) (64% at 48 hours); less preG(1) increase was observed in response to Ly + Te (25%) or Ly + Ca (14%). In p53(-/-) cells, Ly + Te + Ca caused cell accumulation in PreG(1) and G(2)/M phases. In response to the three components, 58% apoptosis occurred in p53(+/+) cells and 38% in p53(-/-) cells. Apoptosis by Ly + Te + Ca, in p53+/+ cells, was associated with increased Bax/Bcl-2 ratio and pp53/p53 ratio, cleavage and activation of caspase-3, loss of mitochondrial membrane potential and cytochrome c release. In p53(-/-) cells, the disruption of mitochondrial membrane potential was observed but to a lesser extent than in p53(+/+) cells and caspase activation or cleavage did not appear to be involved in drug-induced apoptosis. Sage components induced poly(ADP-ribose)-polymerase (PARP) cleavage in both p53(+/+) and p53(-/-) cell lines. Pretreatment with the caspase-3 inhibitor and pan caspase inhibitor abrogated drug-mediated apoptosis and blocked procaspase-3 activation and partially blocked PARP cleavage in p53(+/+) cells. Conversely, in p53(-/-) cells, pre-incubation with caspase inhibitors potentiated drug-induced cell death. It appears that apoptosis in p53(+/+) cells is through the mitochondrial-mediated, caspase-dependent pathway, while in p53(-/-) cells apoptosis is mostly caspase independent despite the presence and features indicating caspase-dependent cell death, such as cytochrome c release and PARP cleavage. Our findings encourage further studies of sage oil components as promising chemotherapeutic agents against colon cancer.
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PMID:Anti colon cancer components from Lebanese sage (Salvia libanotica) essential oil: Mechanistic basis. 1878 2

This study examined the apoptotic effects of crude saponins acquired from the roots of Platycodon grandiflorum (SPR) in HT-29 human colon cancer cells. SPR decreased HT-29 cell proliferation in dose- and time-dependent manners by inducing apoptosis via DNA fragmentation and poly (ADP-ribose) polymerase (PARP) cleavage. The apoptosis induced by SPR was associated with the activation of initiator caspases-8 and -9, as well as the effector caspase-3. SPR stimulated Bid cleavage, indicating that the apoptotic action of caspase-8-mediated Bid cleavage leads to the activation of caspase-9. SPR increased the expression of the pro-apoptotic protein, Bax, and decreased the expression of the anti-apoptotic protein, Bcl-2. SPR also increased the expression of the caspase-independent mitochondrial apoptosis factor, AIF, in HT-29 cells. These results indicate that SPR inhibits HT-29 cell proliferation by inducing apoptosis, which may be mediated via both caspase-dependent and -independent pathways.
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PMID:Induction of apoptosis in HT-29 colon cancer cells by crude saponin from Platycodi Radix. 1895 3


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