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)

Flavopiridol is one of the first cyclin-dependent kinase inhibitors undergoing clinical tests. We found that the combination treatment of flavopiridol (100-500 nM) with tumor necrosis factor (TNF)-alpha (10 ng/ml) induced a rapid and eminent apoptosis, 20 +/- 5% in 6-h treatment, in a human non-small cell lung carcinoma cell line, A549, as determined by the increase of sub-G(1) fraction in flow cytometry. A similar observation was also made in human colon cancer cell lines, HCT-116 and HCT-15, but not in Rat2, a rat fibroblast cell line. In A549 cells, the cytotoxic synergy by the combination treatment involved the activation of caspase-1, caspase-3, and caspase-8 and generated huge chromosomal degradation. The treatment schedules were so important that only the treatments of flavopiridol concomitantly with or followed by TNF-alpha showed the pronounced apoptosis in A549 cells. Prior treatment of TNF-alpha inhibited the apoptosis by the following combination treatment, leading to little cell death. Yet, such inhibition was reversed when 100 microM of 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole, a transcription inhibitor, was present during the TNF-alpha pretreatment, suggesting that the inhibitory pretreatment of TNF-alpha might involve antiapoptotic gene expression at the transcriptional level. TNF-alpha treatment resulted in nuclear factor (NF)-kappa B activation, revealed by NF-kappa B activity reporter assay. In contrast, flavopiridol was found to inhibit the NF-kappa B-dependent gene transcription, which might give an explanation for the synergistic effect of flavopiridol with TNF-alpha. TNF-related apoptosis-inducing ligand (TRAIL; 100 ng/ml) also caused a rapid and strong cytotoxic synergy with flavopiridol. In contrast to TNF-alpha, however, all of the treatment sequences supported the synergy by TRAIL and flavopiridol. The combination of flavopiridol with TNF-alpha or TRAIL may be of use for the development in cancer therapy.
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PMID:Rapid induction of apoptosis by combination of flavopiridol and tumor necrosis factor (TNF)-alpha or TNF-related apoptosis-inducing ligand in human cancer cell lines. 1256 5

Endothelin (ET)-1 can act as an autocrine/paracrine growth factor or an antiapoptotic factor in human cancers. To study the role of ET-1 in human colon cancer, proliferation and apoptosis of colon carcinoma cells was investigated using human HT-29 and SW480 colon carcinoma cells. ET-1 was secreted by these cells. Treatment of cells with bosentan, a dual ET(A/B)-receptor antagonist, decreased cell number. Inhibition of DNA synthesis by bosentan was observed only in the presence of serum. Exogenously added ET-1 did not increase DNA synthesis in serum-deprived cells. SW480 cells were sensitive and HT-29 cells were resistant to FasL-induced apoptosis. Bosentan sensitised resistant HT-29 cells to FasL-induced, caspase-mediated apoptosis, but not to TNF-alpha-induced apoptosis. Bosentan and/or FasLigand (FasL) did not modulate the expression of caspase-8 or FLIP. Bosentan sensitisation to apoptosis was reversed by low concentrations (10(-13)-10(-10) M), but not by high concentrations (10(-9)-10(-7) M) of ET-1. These results suggest that the binding of ET-1 to high-affinity sites inhibits FasL-induced apoptosis, while the binding of either ET-1 or receptor antagonists to low-affinity sites promotes FasL-induced apoptosis. In conclusion, endothelin signalling pathways do not induce human colon cancer cell proliferation, but are survival signals controling resistance to apoptosis.
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PMID:Endothelin-receptor antagonists are proapoptotic and antiproliferative in human colon cancer cells. 1261 91

Dendritic cells (DC) are the most potent antigen-presenting cells known, currently tested for vaccination studies in cancer patients. The use of tumor-derived RNA to load DC overcomes the requirement of defined HLA types and the identification of tumor antigens expressed by the tumors. Here, we show that human monocyte-derived DC generated under serum-free conditions by GM-CSF, IL-4 and TNF-alpha acquire a mature phenotype and expression of the chemokine receptor CCR-7, which plays a pivotal role in DC migration to the afferent lymph nodes. We demonstrate the feasibility of total RNA transfection into such DC using the renal cell carcinoma (RCC) cell line N43-EGFP, which was stably transfected with an EGFP-encoding vector. Moreover, we show that DC transfected with RNA from colorectal cancer cells present HLA class I-restricted antigenic epitopes to induce a primary antitumor CTL response in vitro. Interestingly, the CTL induced by SW480 RNA also recognized another colon cancer line, HCT116, and the RCC line A498. Our results confirm the feasibility of total RNA transfection of serum-free generated DC for the induction of CTL against colon cancer and RCC cells, and support the relevance of shared tumor rejection epitopes between colorectal cancer and RCC.
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PMID:Dendritic cells transfected with tumor RNA for the induction of antitumor CTL in colorectal cancer. 1263 42

Cell-mediated immune responses are an essential aspect of tumour-host interactions in colorectal cancers. The progression from precancerous (adenomatous) colon polyps to malignant colorectal cancer depends on a complex pathway involving the activities of activated T lymphocytes. The immune response is initiated when either cytotoxic T lymphocyte (CTL) CD8+ cells or CD4+ T-helper cells recognize the antigen from a human cancer cell. The cell-mediated response is largely initiated and controlled by the actions of various cytokines, which exert profound effects on T cell proliferation, cell-cell adhesion, apoptosis, and host immunity. The existence of an immune response to colon cancer is supported by studies of immunological treatments in humans and transplantable murine cancer models in animals. IL-2, IL-12, IFN-gamma, TNF-alpha, and TRAIL are implicated in enhancing cytotoxic and apoptotic effects in response to colon adenomas. In addition, growth factors, oncogenic cytokines and immunosuppressive factors may play a crucial role in the growth and survival of premaligant colonic tissue. This review aims to increase knowledge of the immunological mechanisms underlying colon tumour progression in the hopes that a greater understanding of the molecular pathways will lead to improved methods of prognosis and treatment.
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PMID:Colon polyps and cytokines: emerging immunological mechanisms. 1450 22

The immunosuppressive cytokine IL-10 is associated with poor prognosis in colon cancer. Although macrophages are involved in antitumor defenses, production of IL-10 by tumor cells may permit malignant cells escape to cell-mediated immune defenses. To investigate interactions between macrophages and tumor cells in humans, we cultured macrophages isolated from patients and tested the effect of these macrophages on the production of IL-10 by several tumor cell lines. Macrophages were isolated from pleural effusions of patients with malignancy and from noncancer control patients. We demonstrated that culture supernatants of macrophages from both sources strongly stimulated IL-10 production by the three different human colon adenocarcinoma cell lines, Colo 205, Colo 320, and HT29. Recombinant IL-6, but not IL-10, TNF-alpha, and IFN-alpha, stimulated the secretion of IL-10 by colon tumor cells. mAbs against IL-6 and IL-6R prevented the effect of macrophage culture supernatants and of rIL-6, respectively, on the production of IL-10 by the three cell lines. Cocultures of macrophages and colon cancer cells showed that these tumor cells first stimulated macrophages to produce IL-6, which was then followed by IL-6-induced IL-10 production by colon cancer cells. Finally, we showed that IL-10 gene regulation was mediated by STAT3, which was phosphorylated after the binding of IL-6 to IL-6R. This is the first demonstration that IL-6, secreted by macrophages, can induce a STAT3-mediated IL-10 production by colon tumor cells.
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PMID:Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6. 1503 82

Cox-2 plays an important role in colon carcinogenesis and inflammation. Studying the HT-29 colon cancer cell line as a model, we found that Cox-2 expression and activity is increased approximately 25-fold by TNF-alpha. As previously reported for other Cox-2 inducers, this activation appears to result from a p38-mediated mRNA stabilization rather than an increase in promoter activity. The HDAC inhibitors butyrate and TSA blocked the TNF-alpha activation of Cox-2 protein and mRNA synthesis, and dramatically suppressed Cox-2 activity in HT-29 cells. The suppression of Cox-2 synthesis did not involve promoter inactivation and could be achieved even when applied after the TNF-alpha stimulus. The effect of the HDAC inhibitors was observed prior to the activation of p21 expression and did not require new protein synthesis. Finally, butyrate did not prevent p38 phosphorylation, so the block is likely to occur at a later step in the activation pathway. We propose that a component of the cytokine-induced Cox-2 mRNA stabilization pathway is sensitive to acetylation.
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PMID:Butyrate suppresses Cox-2 activation in colon cancer cells through HDAC inhibition. 1506 80

Autologous tumor cells stimulated with T lymphocytes (AuTL) were generated ex vivo from peripheral blood lymphocytes over a two-week co-culturing process with autologous tumor cells. These AuTLs were capable of lysing established tumor cell lines and may have a potential for efficacy as an adoptive immunotherapy (IT) in advanced and metastatic refractory cancer patients (pts). We investigated the feasibility of a combination of AuTL transfer and chemotherapy (ChT) based on the conventional conditioning regimen in order to take advantage by both the anticancer effects and reconstruction of antitumor immunity. Nineteen patients were enrolled in a pilot clinical trial. The two administrations of AuTL were given prior to chemotherapy (ChT) for one treatment cycle. The treatment was repeated at least for three cycles over a one-week interval. The conventional ChT regimen was based on the standard dosage. The pts consisted of 3 of gastric cancer, colon cancer, lung adenocarcinoma, respectively, 6 of esophageal cancer, and 2 of breast and pancreas carcinoma, respectively. AuTLs were administered 1x/2 weeks using direct injection or intraarterial infusion. The median duration of the treatment was over 11.5 months, and the median survival time was 14.8 months. Adverse events related to both the ChT and AuTL transfers at all dosages were minimal. Four of the 13 pts achieved major tumor responses (2 CR: complete regression and 2 PR: partial regression) in this study. Three pts showed progressive disease, and 6 pts had stable disease for over 90 days. PBMC were evaluated for cytokine production prior to the treatment and after 3 treatments. Two and one of 4 CR/PR pts had increased IFN-gamma and TNF-alpha production with no TGF-beta1 responses by their PBMC after 3 treatments, respectively. Two out of 6 pts who experienced stable disease after the treatment had high IFN-gamma and TNF-alpha responses and no TGF-beta1 or IL-4 response. TGF-beta1 and IL-4 secretion increased in parallel in 3 out of 3 pts that experienced progressive disease after the treatment. These data show that combination therapy of AuTL transfer and non-myeloablative ChT is a feasible option for patients with refractory advanced cancers without serious adverse events and without reducing Th1 cytokine responses in peripheral blood for most of the pts that responded to the treatment. According to each mechanism of IT and ChT, a more stringent evaluation of AuTL transfer combined with non-myeloablative ChT for various kinds of cancers should be performed to manage the immunodeficiency in the pts with advanced cancer and to improve the effect of antitumor AuTLs.
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PMID:[The repetitive immune cell transfer therapy combining non-myelosuppressive chemotherapy for patients with advanced and refractory cancer]. 1555 72

Inoculation of a live attenuated herpes simplex virus (HSV) vector, betaH1, into human U87MG glioblastoma cells transplanted into athymic nude mice induced complete regression of tumors. The infected cells underwent histochemically confirmed apoptosis without lymphocyte infiltration after expressing CD30, CD30 ligand (CD30L), tumor necrosis factor (TNF)-alpha, TNF receptor 1 (TNF-R1), FAS, and FAS ligand (FAS-L) with activation of caspases 3 and 8. Induction of the transcripts of these receptors and ligands in inoculated tumors was confirmed by quantitative RT-PCR. To examine the specificity of apoptosis in the transplanted tumor, we inoculated betaH1 into transplanted human lung, breast, gastric, and colon cancer tumors, and similar tumor regression with apoptosis was observed in all tumors. We analyzed the roles of expression of CD30, CD30L, TNF-alpha, TNF-R1, FAS, and FAS-L in the tumors, and found that HSV-induced apoptosis was suppressed by the respective antibodies. These findings indicate that the CD30/CD30L, TNF-alpha/TNF-R1, and FAS/FAS-L interactions resulted in apoptosis and tumor regression in immunocompromised mice. In addition to the death receptor-dependent apoptosis induced by HSV, the expressed ligands and receptors might enhance the susceptibility of tumor cells to cell-mediated cyto-toxicity and augment the activation of tumor-killing lymphocytes in immunocompetent models.
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PMID:Herpes simplex virus-induced, death receptor-dependent apoptosis and regression of transplanted human cancers. 1559 49

The molecular mechanisms responsible for TNF-alpha-mediated MUC2 intestinal mucin up-regulation in HM3 colon adenocarcinoma cells were analyzed using promoter-reporter assays of the 5'-flanking region of the MUC2 gene. Chemical inhibitors, mutant reporter constructs, and EMSA confirmed I-kappaB/NF-kappaB pathway involvement. Wortmannin, LY294002 and dominant negative Akt, as well as dominant negative NF-kappaB-inducing kinase (NIK) inhibited MUC2 reporter transcription, indicating that both phosphatidylinositol-3-OH kinase (PI3K)/Akt signaling pathway and NIK pathways mediate the effects of TNF-alpha. Wortmannin inhibited NF-kappaB binding and transcriptional activity without inhibiting NF-kappaB translocation to the nucleus, indicating that PI3K/Akt signaling activates NF-kappaB transcriptional activity directly. Our results demonstrate that TNF-alpha up-regulates MUC2 in human colon epithelial cells via several signaling pathways, involving both NIK and PI3K/Akt, which converge at the common IKK/I-kappaB/NF-kappaB pathway. TNF-alpha activated JNK, but JNK inhibitor SP600125 and dominant negative cJun consistently activated transcription, revealing a negative role for this signaling pathway. Thus TNF-alpha causes a net up-regulation of MUC2 gene expression in cultured colon cancer cells because NF-kappaB transcriptional activation of this gene is able to counter-balance the suppressive effects of the JNK pathway. However, the existence of this inhibitory JNK pathways suggests a mechanism whereby--in the absence of NF-kappaB activation--TNF-alpha production during inflammation in vivo could actually inhibit MUC2 production, giving rise to the defective mucosal protection which characterizes inflammatory bowel disease.
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PMID:TNF-alpha activates MUC2 transcription via NF-kappaB but inhibits via JNK activation. 1566 13

The transcription factor NF-kappa B is constitutively activated in many human cancers, and induces the expression of multiple proteins including antiapoptotic proteins. Recent papers indicate that NF-kappa B activation is inhibited by interleukin (IL)-10. In this study, we investigated the effect of IL-10 plasmid DNA on colon cancer in mice. In vitro study: Colon 26 murine colon adenocarcinoma cells were either treated or untreated with IL-10 for 60 min. The cells were subsequently stimulated with TNF-alpha. In vivo study: to induce a high level of IL-10 in plasma, we transferred the naked plasmid vectors encoding the mouse IL-10 gene into the liver via the intravenous route. To establish tumors, we injected Colon 26 cells into BALB/c mice subcutaneously. In vitro study: a 24-h incubation with TNF-alpha did not affect cell viabilities; however, pretreatment with IL-10 significantly enhanced the level of apoptosis induced by TNF-alpha. Pretreating Colon 26 cells with IL-10 significantly attenuated the TNF-alpha-induced NF-kappa B activation. In vivo study: IL-10 plasmid controlled the growth of subcutaneous tumors. In subcutaneous tumor, NF-kappa B was activated in response to tumor growth. IL-10 plasmid markedly inhibited this activation of NF-kappa B in subcutaneous tumor. IL-10 plasmid induced cancer cell apoptosis linked to the down-regulation of antiapoptotic proteins, and the activation of caspase-3. These results demonstrate that IL-10 plasmid may constitute a new strategy for treating cancer growth.
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PMID:Interleukin-10 plasmid DNA inhibits subcutaneous tumor growth of Colon 26 adenocarcinoma in mice. 1567 Aug 94


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