Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In a search for new anticancer agents, we identified that 2[[3-(2,3-dichlorophenoxy) propyl]amino]ethanol (2,3-DCPE) induced apoptosis more effectively in various cancer cells than in normal human fibroblasts. We further evaluated the cell-killing effects of this compound in vitro in several human cancer cell lines and normal human fibroblasts. A cell viability assay showed that IC(50)s for human colon cancer cell lines LoVo and DLD-1, for human lung cancer cell lines H1299 and A549, and for normal human fibroblasts were 0.89, 1.95, 2.24, 2.69, and 12.6 micro M, respectively. Subsequent studies revealed that 2,3-DCPE could cause cleavage of caspase-8, caspase-3, caspase-9, and poly(ADP-ribose) polymerase and release of cytochrome c in cancer cells but not in normal human fibroblasts. Our data also showed that 2,3-DCPE attenuated the protein level of Bcl-XL and that apoptosis induction by 2,3-DCPE could be blocked by enforced overexpression of Bcl-XL. Our results suggest that 2,3-DCPE might be a potential new anticancer agent.
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PMID:Induction of apoptosis and down-regulation of Bcl-XL in cancer cells by a novel small molecule, 2[[3-(2,3-dichlorophenoxy)propyl]amino]ethanol. 1487 45

As previously demonstrated, the synthetic bile acid derivatives mediate anti-proliferative properties in a variety of human cancer cells. In the present study, the effects of the synthetic derivatives of ursodeoxycholic acid (UDCA), HS-1030 and HS-1183, and chenodeoxycholic acid (CDCA), HS-1199 and HS-1200, on the proliferation of HT-29 human colon cancer cells were investigated. Whereas UDCA and CDCA had no effect on the growth of cells in the concentration ranges we have tested, HS-1199 and HS-1200 completely inhibited cell proliferation, while HS-1030 and HS-1183 showed weak inhibitory activities. Simultaneous estimation of cell cycle parameters and apoptosis by flow cytometry showed that the synthetic bile acid derivatives produced the arrest of cell cycle progression at the G1 phase and ensuing increase of sub-G1 fraction, which resulted in the induction of apoptosis. The induction of apoptosis was confirmed by observation of cleavages of poly(ADP-ribose) polymerase and DNA fragmentation. Furthermore, Western blot analysis showed decreased expression levels of cyclin D1, cyclin E, cyclin A, Cdk2, Cdk4, and Cdk6 proteins. In addition, the synthetic bile acid derivatives markedly induced the level of Cdk inhibitor, p21WAF1/CIP1, in a p53-independent manner. Furthermore, the exposure of cells to the synthetic bile acid derivatives resulted in a decrease in the level of pRb and enhanced binding between pRb and E2F-1. Based on these data, these synthetic bile acid derivatives may serve as potential lead compounds in the treatment of colon cancer.
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PMID:Synthetic bile acid derivatives inhibit cell proliferation and induce apoptosis in HT-29 human colon cancer cells. 1520 11

2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and the corresponding methyl (CDDO-Me) and imidazole (CDDO-Im) esters induce peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent transactivation in SW-480 colon cancer cells, and these responses were inhibited by small inhibitory RNA for PPARgamma. Moreover, in a mammalian two-hybrid assay using the PPARgamma(2)-VP16 fusion plasmid and GAL4-coactivator/corepressor chimeras and a construct (pGAL4) containing five tandem GAL4 response elements, CDDO, CDDO-Me, and CDDO-IM induce transactivation and PPARgamma interaction with multiple coactivators. A major difference among the three PPARgamma agonists was the higher activity of CDDO-Im to induce PPARgamma interactions with the corepressor SMRT. CDDO, CDDO-Me, and CDDO-Im inhibited SW-480, HCT-116, and HT-29 colon cancer cell proliferation at low concentrations and induced cell death at higher concentrations. Growth inhibition at lower concentrations correlated with induction of the tumor suppressor gene caveolin-1 which is known to inhibit colon cancer cell growth. Induction of caveolin-1 by CDDO, CDDO-Me, and CDDO-Im was inhibited by the PPARgamma antagonist N-(4'-aminopyridyl-2-chloro-5-nitrobenzamide (T007), whereas higher doses induced apoptosis [poly(ADP-ribose) polymerase cleavage], which was not inhibited by T007. These results illustrate that CDDO-, CDDO-Me, and CDDO-Im induce both PPARgamma-dependent and -independent responses in colon cancer cells, and activation of these pathways are separable and concentration-dependent for all three compounds.
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PMID:2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid and related compounds inhibit growth of colon cancer cells through peroxisome proliferator-activated receptor gamma-dependent and -independent pathways. 1579 84

Sulindac is one of the most widely studied nonsteroidal anti-inflammatory drugs in the prevention of colon cancer. Thus, from the viewpoint of colon cancer chemotherapy it is important to reveal the mechanism of sulindac-induced cell death. This study was undertaken to dissect the molecular mechanism underlying sulindac-induced apoptosis in human colon cancer cell line HT-29 (mutant p53), focusing on nuclear translocation of AIF, DFF and endonuclease G. On induction of apoptosis by sulindac, it was associated with decreased mitochondrial membrane potential, nuclear expression of active caspase-3, cleavage of poly(ADP-ribose) polymerase, translocation of mitochondrial proteins to the nucleus, and morphological evidence of nuclear condensation. However, sulindac led to only disintegration of nuclear DNA into high molecular weight DNA fragments of about 100-300 kbp as determined by a pulse-field gel electrophoresis, suggesting a predominantly AIF-mediated cell death process. In summary, our findings indicate that sulindac induces large-scale DNA fragmentation without oligonucleosomal DNA fragmentation. This result suggests that nuclear translocation of DFF and endonuclease G are not sufficient for the induction of oligonucleosomal DNA fragmentation in HT-29 cells.
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PMID:Sulindac activates nuclear translocation of AIF, DFF40 and endonuclease G but not induces oligonucleosomal DNA fragmentation in HT-29 cells. 1594 92

We previously showed that panduratin A isolated from an extract of Kaempferia pandurata (Zingiberaceae) was a strong inhibitor of cyclooxygenase-2 (COX-2) in RAW264.7 cells, suggesting a potential use of panduratin A as an anti-inflammatory agent. In the present study, we have investigated the effects of panduratin A on cytoplasmic levels of COX-2, as well as proliferation and apoptosis in human colon cancer cells HT-29. Cell proliferation and induction of apoptosis was determined by the MTT assay, DNA fragmentation measurement, flow cytometric analysis, nuclear staining and Western blotting. The MTT assay indicated that panduratin A exhibited cytotoxicity with an IC50 value of 28 microM. The cytotoxic effects of panduratin A were found to be accompanied by the dose-dependent induction of apoptosis as assessed by DNA fragmentation and apoptotic bodies. In addition, treatment with an apoptosis-inducing concentration of panduratin A resulted in cleavage of poly(ADP-ribose) polymerase (PARP) with a concomitant decrease in procaspase-3 protein. Our study provides evidence for cell growth inhibition and induction of apoptosis by panduratin A in human colon cancer cells, suggesting its potential use as a cancer chemopreventive and therapeutic agent.
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PMID:Induction of apoptosis by Panduratin A isolated from Kaempferia pandurata in human colon cancer HT-29 cells. 1597 Nov 19

Previous studies have shown that constitutive activation of epidermal growth factor receptor (EGFR) and ErbB2 by elevated autocrine transforming growth factor-alpha (TGF-alpha) expression plays an important role in colon cancer progression. Coexpression of EGFR and ErbB2 is found in a subset of colon cancers and may cooperatively promote cancer cell growth and survival, as heterodimerization is known to provide for diversification of signal transduction. In this study, the EGFR-selective tyrosine kinase inhibitor (TKI) AG1478 inhibited cell growth of an aggressive human colon carcinoma cell line, FET6alphaS26X, which harbors constitutively activated EGFR after stable transfection with TGF-alpha cDNA. However, AG1478 failed to induce apoptosis in FET6alphaS26X cells at concentrations sufficient for cell growth inhibition and complete suppression of EGFR phosphorylation. Similarly, AG879, a selective ErbB2 TKI, was incapable of inducing apoptosis in FET6alphaS26X cells at concentrations sufficient to inhibit cell growth and ErbB2 phosphorylation. To test the hypothesis that targeting both ErbB family members would show better efficacy than targeting the single receptors, combinations of inhibitors at fixed ratios of 1:1, 5:1, and 10:1 of AG1478 and AG879, respectively, were compared with single drugs for inhibition of cell growth. All combinations resulted in synergistic effects as indicated by combination index analysis. Synergistic inhibition was associated with induction of apoptosis as reflected by poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Annexin V staining. Finally, Western blot analysis showed significant inhibition of phosphorylation of both EGFR and ErbB2 by the combination treatment. These data suggest that the strategy to target both EGFR and ErbB2 simultaneously might result in more efficient inhibition of tumor growth than to target single receptor alone.
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PMID:Synergy of epidermal growth factor receptor kinase inhibitor AG1478 and ErbB2 kinase inhibitor AG879 in human colon carcinoma cells is associated with induction of apoptosis. 1599 62

Proteasome inhibitors can resensitize cells that are resistant to tumor necrosis factor-related apoptotic-inducing ligand (TRAIL)-mediated apoptosis. However, the underlying mechanisms of this effect are unclear. To characterize the mechanisms of interaction between proteasome inhibitors and TRAIL protein, we evaluated the effects of combined treatment with the proteasome inhibitors bortezomib and MG132 and TRAIL protein on two TRAIL-resistant human colon cancer cell lines, DLD1-TRAIL/R and LOVO-TRAIL/R. Both bortezomib and MG132 in combination with TRAIL enhanced apoptotosis induction in these cells, as evidenced by enhanced cleavage of caspases 8, 9, and 3, Bid, poly(ADP-ribose) polymerase and by the release of cytochrome C and Smac. Subsequent studies showed that combined treatment with bortezomib or MG132 resulted in an increase of death receptor (DR) 5 and Bik at protein levels but had no effects on protein levels of DR4, Bax, Bak, Bcl-2, Bcl-XL or Flice-inhibitory protein (FLIP). Moreover, c-Jun N-terminal kinase (JNK) is activated by these proteasome inhibitors. Blocking JNK activation with the JNK inhibitor SP600125 attenuated DR5 increase, but enhancement of apoptosis induction and increase of Bik protein were not affected. However, bortezomib-mediated TRAIL sensitization was partially blocked by using siRNA to knockdown Bik. Thus, our data suggests that accumulation of Bik may be critical for proteasome inhibitor-mediated resensitization of TRAIL.
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PMID:Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation. 1608 82

We previously reported that the garlic-derived compound S-allylmercaptocysteine (SAMC) causes growth inhibition, mitotic arrest, and induction of apoptosis in SW480 human colon cancer cells by inducing microtubule depolymerization and c-Jun NH(2) terminus kinase-1 activation. In the present study, we compared the aforementioned effects of SAMC to those of a series of garlic-derived and other organosulfur compounds. Among the 10 compounds tested, only SAMC, diallyl disulfide (DADS), and S-trityl-L-cysteine (trityl-cys) cause significant inhibition of cell growth with IC(50) values of 150, 56, and 0.9 micromol/L, respectively. These three compounds also induce G(2)-M cell cycle arrest and apoptosis. Further studies reveal that, like SAMC, the garlic-derived compound DADS exerts antiproliferative effects by binding directly to tubulin and disrupting the microtubule assembly, thus arresting cells in mitosis and triggering mitochondria-mediated signaling pathways that lead to apoptosis. However, the synthetic compound trityl-cys exerts its effect on M-phase arrest and growth inhibition by mechanisms that involve spindle impairment but do not involve disruption of microtubule structure or dynamics. Furthermore, trityl-cys does not induce marked loss of mitochondrial membrane potential or release of cytochrome c, but it does induce caspase-3 activation and poly(ADP-ribose) polymerase cleavage. Structure-function analysis suggests that both the allyl and the disulfide moieties are important features for the antiproliferative effects of SAMC and DADS. These findings may be useful in the identification, synthesis, and development of organosulfur compounds that have anticancer activity.
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PMID:Effects of a series of organosulfur compounds on mitotic arrest and induction of apoptosis in colon cancer cells. 1617 31

The c-myc oncogene encodes for a transcriptional factor involved in many cellular processes such as proliferation, differentiation and apoptosis. According to these different functions, the role of c-Myc protein in cellular sensitivity to anti-cancer drugs is controversial. We defined the role of c-Myc in cancer cell sensitivity to vinblastine (VLB) using human colon cancer cells: LoVo wild-type or transfected with a plasmid containing the human c-myc gene in antisense orientation (LoVo-mycANS). Analysis of VLB cytotoxicity demonstrated a 3-fold increase in VLB sensitivity in LoVo-mycANS cells. Comparison between cells revealed different apoptosis kinetics: accumulation of cells in sub-G1 phase and poly(ADP-ribose) polymerase cleavage occurred earlier in LoVo-mycANS. Then, we demonstrated a mitochondrial membrane potential disruption followed by cytochrome c release that indicates the involvement of mitochondria in this apoptotic signaling pathway. This earlier apoptosis was accompanied by a Bcl-2 decrease and a p53 increase. In conclusion, the decrease in c-Myc expression enhanced the VLB sensitivity, triggering earlier apoptosis through induction of the intrinsic pathway. Thus, c-myc induction is a resistance factor and our findings suggest that tumors carrying low levels of c-Myc protein could be more responsive to vinca alkaloids treatment. Moreover, the downregulation of c-myc oncogene by an antisense strategy might represent a useful goal for improving the efficacy of this anti-neoplastic drug family.
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PMID:Decrease in c-Myc activity enhances cancer cell sensitivity to vinblastine. 1642 36

Luteolin is 3',4',5,7-tetrahydroxyflavone found in celery, green pepper, and perilla leaf that inhibits tumorigenesis in animal models. We examined luteolin-mediated regulation of cell cycle progression and apoptosis in the HT-29 human colon cancer cell line. Luteolin decreased DNA synthesis and viable HT-29 cell numbers in a concentration-dependent manner. It inhibited cyclin-dependent kinase (CDK)4 and CDK2 activity, resulting in G1 arrest with a concomitant decrease of phosphorylation of retinoblastoma protein. Activities of CDK4 and CDK2 decreased within 2 h after luteolin treatment, with a 38% decrease in CDK2 activity (P < 0.05) observed in cells treated with 40 micromol/l luteolin. Luteolin inhibited CDK2 activity in a cell-free system, suggesting that it directly inhibits CDK2. Cyclin D1 levels decreased after luteolin treatment, although no changes in expression of cyclin A, cyclin E, CDK4, or CDK2 were detected. Luteolin also promoted G2/M arrest at 24 h posttreatment by downregulating cyclin B1 expression and inhibiting cell division cycle (CDC)2 activity. Luteolin promoted apoptosis with increased activation of caspases 3, 7, and 9 and enhanced poly(ADP-ribose) polymerase cleavage and decreased expression of p21(CIP1/WAF1), survivin, Mcl-1, Bcl-x(L), and Mdm-2. Decreased expression of these key antiapoptotic proteins could contribute to the increase in p53-independent apoptosis that was observed in HT-29 cells. We demonstrate that luteolin promotes both cell cycle arrest and apoptosis in the HT-29 colon cancer cell line, providing insight about the mechanisms underlying its antitumorigenic activities.
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PMID:Induction of cell cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin. 1690 94


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