Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Survivin is expressed in most human neoplasms, but is absent in normal, differentiated tissues. Survivin is a bifunctional inhibitor of apoptosis protein that has been implicated in protection from apoptosis and regulation of mitosis. Several clinical trials targeting survivin with a collection of different approaches from small molecule antagonists to immunotherapy are currently under way. With regard to the latter, spontaneous anti-survivin T-cell reactivity has been described in cancer patients suffering from a huge range of cancers of different origin, e.g., breast and colon cancer, lymphoma, leukemia, and melanoma. Thus, survivin may serve as a universal target antigen for anticancer immunotherapy. Accordingly, down-regulation of survivin as a means of immune escape would severely inflict the survival capacity of tumor cells, which highlights this protein as a prime target candidate for therapeutic vaccinations against cancer. Data from several ongoing phase I/II trials targeting survivin for patients with advanced cancer will provide further information about this idea.
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PMID:The universal character of the tumor-associated antigen survivin. 1794 59

Recently, we identified a nucleoside analog named ARC (4-amino-6-hydrazino-7-beta-D-ribofuranosyl-7H-Pyrrolo[2,3-d]pyrimidine-5-carboxamide), which has the properties of a general transcriptional inhibitor. Here, we report the characterization of ARC on a panel of colorectal cancer (CRC) cell lines. Cell death induced by ARC in CRC cells was accompanied by caspase-3 cleavage and correlated with the downregulation of antiapoptotic proteins, survivin and Mcl-1 and with the inhibition of Akt phosphorylation. At the same time, colon cancer cell lines were resistant to the well-known nucleoside analog DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole), which failed to downregulate Mcl-1 or survivin. Overall, ARC could represent an attractive candidate for anti-cancer drug development that targets multiple survival pathways in colon cancer cells.
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PMID:Differential sensitivity of human colon cancer cell lines to the nucleoside analogs ARC and DRB. 1799 11

Recent studies suggest that secreted phospholipases A2 (sPLA2s) represent attractive potential tumour biomarkers and therapeutic targets for various cancers. As a first step to address this issue in human colorectal cancer, we examined the expression of the full set of sPLA2s in sporadic adenocarcinomas and normal matched mucosa from 21 patients by quantitative PCR and immunohistochemistry. In normal colon, PLA2G2A and PLA2G12A were expressed at high levels, PLA2G2D, PLA2G5, PLA2G10 and PLA2G12B at moderate levels, and PLA2G1B, PLA2G2F and PLA2G3 at low levels. In adenocarcinomas from left and right colon, the expression of PLA2G3 was increased by up to 40-fold, while that of PLA2G2D and PLA2G5 was decreased by up to 23- and 14-fold. The variations of expression for sPLA2-IID, sPLA2-III and sPLA2-V were confirmed at the protein level. The expression pattern of these sPLA2s appeared to be linked respectively to the overexpression of interleukin-8, defensin alpha6, survivin and matrilysin, and downregulation of SFRP-1 and RLPA-1, all these genes being associated to colon cancer. This original sPLA2 profile observed in adenocarcinomas highlights the potential role of certain sPLA2s in colon cancer and suggests that sPLA2-III might be a good candidate as a novel biomarker for both left and right colon cancers.
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PMID:Distinct expression pattern of the full set of secreted phospholipases A2 in human colorectal adenocarcinomas: sPLA2-III as a biomarker candidate. 1821 56

SN-38 is an active metabolite of the topoisomerase I inhibitor irinotecan. The mechanism behind its antitumor effect in colorectal cancer is not fully understood. In this study, we examined the response of colon cancer cell lines with different metastatic potential to SN-38. The parental human colon cancer cell line KM12C and its two highly metastatic derivatives KM12SM and KM12L4a were cultivated in 5% CO2 at 37 degrees C for 24 h and then exposed to SN-38 (2.5 microg/ml) at 37 degrees C for 4, 24 and 48 h, respectively. The cell cycle was measured by flow cytometry, apoptotic activity was determined by flow cytometry and immunocytochemistry and the expression of topoisomerase I, Bax and survivin proteins were examined by Western blot. The exposure of the cells to SN-38 induced S-phase and G2 arrest (P<0.0001) and the KM12L4a cells had the highest response in a time-dependent manner (P<0.0001). The rates of apoptosis in the KM12SM (P=0.001) and KM12L4a cell lines (P=0.01) were increased time-dependently, though there was no such change in the KM12C cells. The expression of topoisomerase I protein was decreased in each cell line tested and the expression of Bax protein was increased, especially in KM12L4a. In conclusion, the effect of SN-38 on the colon cancer cell lines was mediated via conducting S-phase and G2 arrest and apoptosis. This effect was found in the cell lines with higher metastatic potentials, indicating that SN-38 can be used to treat advanced colon cancers.
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PMID:Anticancer effect of SN-38 on colon cancer cell lines with different metastatic potential. 1849 55

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

Ca(2+) and the cell-surface calcium sensing receptor (CaSR) constitute a novel and robust ligand/receptor system in regulating the proliferation and differentiation of colonic epithelial cells. Here we show that activation of CaSR by extracellular Ca(2+) (or CaSR agonists) enhanced the sensitivity of human colon carcinoma cells to mitomycin C (MMC) and fluorouracil (5-FU). Activation of CaSR up-regulated the expression of MMC activating enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO-1) and down-regulated the expression of 5-FU target, thymidylate synthase (TS) and the anti-apoptotic protein survivin. Cells that were resistant to drugs expressed little or no CaSR but abundant amount of survivin. Disruption of CaSR expression by shRNA targeting the CaSR abrogated these modulating effects of CaSR activation on the expression of NQO1, TS, survivin and cytotoxic response to drugs. It is concluded that activation of CaSR can enhance colon cancer cell sensitivity to MMC and 5-FU and can modulate the expression of molecules involved in the cellular responses to these cytotoxic drugs.
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PMID:Calcium and calcium sensing receptor modulates the expression of thymidylate synthase, NAD(P)H:quinone oxidoreductase 1 and survivin in human colon carcinoma cells: promotion of cytotoxic response to mitomycin C and fluorouracil. 1861 19

Tamoxifen has been the mainstay of endocrine therapy for estrogen receptor-positive breast cancer. However, approximately 40% of breast cancer patients do not respond to tamoxifen treatment. Further, most tumors eventually acquire tamoxifen resistance. Therefore, it is necessary to develop effective modalities to enhance the efficacy of tamoxifen in breast cancer treatment. In this study, we investigated the mechanism by which breast cancer cells develop resistance against tamoxifen from the viewpoint of tamoxifen-induced apoptosis. Overexpression of the anti-apoptotic molecule survivin rendered the human breast cancer cells MCF-7 resistant to tamoxifen-induced apoptosis. To examine whether the down-regulation of survivin can enhance tamoxifen-induced apoptosis, we introduced siRNA targeting the survivin gene (survivin-siRNA) into MCF-7 cells. Survivin-siRNA transfection not only induced apoptosis without tamoxifen treatment but also augmented the tamoxifen-induced apoptosis. We have previously demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs), which are widely used to reduce the serum cholesterol levels in hypercholesterolemia patients, decreases survivin expression in colon cancer cells. To develop a pharmacological approach for improving the efficacy of tamoxifen treatment, we determined whether HRIs can enhance tamoxifen-induced apoptosis. Lovastatin, an HRI, down-regulated the expression of survivin protein in MCF-7 cells in a dose-dependent manner. In addition, the proportion of apoptotic cells induced by the tamoxifen and lovastatin combination was greater than the theoretical additive effect. These results suggest that survivin may function as a factor inducing resistance against tamoxifen-induced apoptosis, and the combined use of tamoxifen and HRI may be a novel approach to overcome tamoxifen resistance in breast cancer.
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PMID:Survivin plays as a resistant factor against tamoxifen-induced apoptosis in human breast cancer cells. 1881 81

Survivin is an attractive candidate for cancer immunotherapy since it is overexpressed in most common human cancers, poorly expressed in most normal adult tissues and is essential for cancer cell survival. Previously, we and others have demonstrated that survivin-specific immune responses are present in cancer patients. However, a significant limitation of these findings has been that antigen-specific lysis of tumors was achieved using polyclonal T-cell lines rather than a specific T-cell clone. In the present study we isolated and expanded a survivin specific cytotoxic T lymphocyte (CTL) clone from the peripheral blood of a cancer patient. The survivin specific CTL clone efficiently lysed a large panel of tumor cells of different origin, i.e., breast cancer, colon cancer and melanoma cells. The data support the notion that survivin may serve as a universal target antigen for anti-cancer immunotherapy.
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PMID:A survivin specific T-cell clone from a breast cancer patient display universal tumor cell lysis. 1915 76

Novel demethylcantharidin-platinum (DMC-Pt) complexes have been found to have superior in vitro anticancer activity against a number of human colon cancer cell lines when compared with oxaliplatin. One complex where the DMC-Pt moiety was integrated with trans-R,R-diamino-cyclohexane (DACH), exhibited the most pronounced cytotoxicity. To ascertain the mechanistic contribution of the DMC component, microarray analysis was conducted to compare the effect of the novel (R,R-DACH)-Pt-(DMC) complex and oxaliplatin, on the gene expression of human colorectal cancer (HCT116) cells. The Affymetrix HG-U133A oligonucleotide microarray was used, and the data allowed for the discrimination of genes that were specifically affected by the DMC ligand. One hundred and forty-one genes were found to be up-regulated. Of these, 48 can be classified according to different cellular responses including DNA repair, DNA synthesis, cell adhesion, cell cycle regulation, mitotic spindle checkpoint and apoptosis/antiapoptosis. The DMC ligand is likely to have caused damage to DNA bases and/or strands, and nucleotide mismatch, as highlighted by the recruitment of the repairing genes from the BER, HR and MMR. Antiapoptotic genes such as survivin, BRCA1 and ITGB3BP were up-regulated, and it is proposed that the inherent defense mechanism of the cell may have been triggered, creating potential resistance to apoptosis. This study is the first to demonstrate the impact of the DMC ligand on the gene expression profile of HCT116 colon cancer cells and further substantiates its inclusion in the design of novel platinum-based anticancer complexes.
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PMID:Impact of oxaliplatin and a novel DACH-platinum complex in the gene expression of HCT116 colon cancer cells. 1894 32

Overexpression of cFLIP protein seems to be critical in the antiapoptotic mechanism of immune escape of human COLO 205 colon adenocarcinoma cells. Actually, cFLIP appears to inhibit the death receptor ligand-mediated cell death. Application of the metabolic inhibitor sodium butyrate (NaBt), short-chain volatile fatty acid, sensitized COLO 205 cells to TNF-alpha-mediated apoptosis. Western-blot analysis revealed that the susceptibility of human COLO 205 cells to apoptogenic stimuli resulted from time-dependent reduction in cFLIP and simultaneous up-regulation of TNF-R1 protein levels. Additionally, the combined TNF-alpha and NaBt treatment caused cleavage of Bid and caspase-9 activation, as well as cytochrome c release from mitochondria. Thus, the evidence of this study indicates that NaBt facilitates the death receptor signal evoked by TNF-alpha. Moreover, NaBt alone initiated intrinsic apoptosis, that in turn was abolished by intracellular BCL-2 delivery. It confirms the involvement of mitochondria in the proapoptotic activity of NaBt. The activation of mitochondrial pathway was substantiated by up-regulated expression of BAK with concomitant reduction of antiapoptotic BCL-x(L), XIAP and survivin proteins. These findings suggest that NaBt could represent a good candidate for the new therapeutic strategy aimed to improve chemo- and immunotherapy of colon cancer.
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PMID:Sodium butyrate sensitizes human colon adenocarcinoma COLO 205 cells to both intrinsic and TNF-alpha-dependent extrinsic apoptosis. 1913 Feb 37


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