Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nuclear transcription factor interferon regulatory factor-1 (IRF-1) is a putative tumor suppressor, but the expression and function of IRF-1 in esophageal adenocarcinoma (EA) remain unknown. We hypothesized that IRF-1 expression was reduced or lost in EA and that restoration of IRF-1 would result in the apoptosis of EA cells in vitro and the inhibition of tumor growth in vivo. Three EA cell lines were used to examine IRF-1 expression, IFN-gamma responsiveness, and the effects of IRF-1 overexpression using a recombinant adenoviral vector (Ad-IRF-1). All three EA cell lines produced IRF-1 protein following IFN-gamma stimulation, although IFN-gamma did not induce cell death. In contrast, Ad-IRF-1 infection resulted in high levels of IRF-1 protein and triggered apoptosis in all three EA cell lines. Potential mechanisms for the differential response to IFN-gamma versus Ad-IRF-1--such as modulation of c-Met or extracellular regulated kinase signaling, or altered expression of IRF-2, Fas, or survivin--were investigated, but none of these mechanisms can account for this observation. In vivo administration of IRF-1 in a murine model of EA modestly inhibited tumor growth, but did not lead to tumor regression. Strategies aimed at increasing or restoring IRF-1 expression may have therapeutic benefits in EA.
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PMID:Ad-IRF-1 induces apoptosis in esophageal adenocarcinoma. 1653 23

The objective of the present study was to determine the influence of cyclooxygenase-2 (COX-2) inhibition by Celecoxib (CLX) in humans with distal colorectal adenocarcinoma (CRC) on serum and tumor levels of progastrin and gastrin and serum levels of proinflammatory cytokines (IL-8, TNF-alpha). In addition, the effects of this CLX treatment on tumor and adjacent mucosa expression of gastrin, its receptors (CCK2), and COX-1 and COX-2, as well as protein expression of the active form of nuclear factor kappa B (NFkappa B) and the apoptotic-related proteins Bcl-2 and survivin, have been examined. Ten distal CRC patients were examined twice, once before and then after 14-day treatment with CLX (200 mg bid). Large biopsy samples were taken from the tumor and intact mucosa 10 cm above the tumor. For comparison, 20 age- and sex-matched healthy controls were enrolled and treated with CLX as CRC patients. Serum levels of IL-8 and TNF-alpha were measured by enzyme-linked immunosorbent assay, and serum levels of amidated gastrins and progastrin, by specific radioimmunoassay. The gene or protein expressions of progastrin, gastrin, CCK2, COX-1, COX-2, Bcl-2, and survivin as well as NFkappa B were determined by RT-PCR or Western blot in biopsy samples of tumor and intact mucosa of CRC patients. Serum IL-8 and TNF-alpha values were severalfold higher in CRC patients than in controls. The increase in serum proinflammatory cytokines was accompanied by increased expression of the active form of NFkappa B. Serum progastrin levels were also found to be significantly higher in CRC than in controls. Treatment of CRC with CLX resulted in a significant decrease in serum levels of progastrin and this was accompanied by an increment in tumor expression of COX-2 with a concomitant reduction in gastrin, Bcl-2, survivin, and NFkappa B expression. We conclude that (1) distal CRC patients show significantly higher serum progastrin levels than matched healthy controls, confirming that this hormone may be implicated in rectal carcinogenesis; (2) CRC patients exhibit significantly higher serum levels of IL-8 and TNF-alpha than healthy controls, probably reflecting more widespread inflammatory reaction in the colonic mucosa in CRC; (3) gastrin, COX-2, Bcl-2, survivin, and NFkappa B were overexpressed in CRC tumor compared to intact mucosa, but treatment with CLX significantly reduced serum levels of progastrin and IL-8 and TNF-alpha, which could mediate the up-regulation of COX-2 in CRC; and (4) CLX also enhanced expression of COX-2, while inhibiting the expression of gastrin, Bcl-2, survivin, and NFkappa B, suggesting that COX-2 inhibition might be useful in chemoprevention against CRC, possibly due to suppression of the antiapoptotic proteins and reduction in progastrin-induced and NFkappa B-promoted tumor growth.
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PMID:Effects of cyclooxygenase-2 inhibition on serum and tumor gastrins and expression of apoptosis-related proteins in colorectal cancer. 1661 3

Survivin is a unique member of the inhibitor of apoptosis (IAP) protein family that interferes with post-mitochondrial events including activation of caspases. Survivin regulates cell cycle also. It is expressed in most of the human tumors, but it is barely detectable in the terminally differentiated normal cells/tissues. Molecular mechanisms of regulation of survivin in cancer are not clearly understood. Nevertheless, the functional loss of wild type p53 is often associated with upregulation of survivin. Tumors that over-express survivin generally bear a poor prognosis and are associated with resistance to therapy. The differential expression of survivin in cancer versus normal tissues makes it a useful tool in cancer diagnosis and a promising therapeutic target. A growing body of literature suggests nuclear expression of survivin as a good prognostic marker. Disruption of the survivin induction pathway has resulted in an increase in apoptosis and inhibition of tumor growth. Regular therapies, such as, radiotherapy in combination with anticancer drugs in clinical practice may yield promising results.
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PMID:Structural, functional and therapeutic biology of survivin. 1662 Dec 43

Despite local and systemic therapies, the National Cancer Institute estimates that prostate cancer will cause over 30,000 deaths in 2006. This suggests that additional therapeutic approaches are needed. The chicken anemia viral protein Apoptin causes tumor-selective apoptosis in human tumor lines independent of p53 and Bcl-2 status. Tet-regulated expression of Apoptin from an adenoviral vector showed cytotoxicity in DU145, PC-3, and LNCaP tumor cells regardless of expression of p53, Bcl-2, Bcl-xL, Bax, survivin, FLIP(S), XIAP, or CIAP. Apoptin expression caused an increase in the tumor suppressor lipid ceramide, which regulates the cellular stress response. Interestingly, 10 of 15 primary prostate cancers examined by Western blotting overexpressed acid ceramidase (AC), suggesting that ceramide deacylation might serve to negate elevated levels of ceramide, creating a more antiapoptotic phenotype. This was confirmed in AC-overexpressing cells in which we observed decreased sensitivity to apoptosis following treatment with Apoptin. Addition of the AC inhibitor LCL204, in combination with Apoptin, augmented cell killing. This effect was also demonstrated in vivo in that Apoptin and LCL204 cotreatment significantly reduced tumor growth in DU145 xenografts (P<0.05). Taken together, our data demonstrated that Apoptin is a promising therapeutic agent for prostate cancer and that its function is improved when combined with acid ceramidase inhibitors.
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PMID:Modulation of ceramide metabolism enhances viral protein apoptin's cytotoxicity in prostate cancer. 1716 68

Several natural compounds, especially plant products and dietary constituents, are able to exhibit 'angiopreventive' (anti-angiogenic chemoprevention) activities both in vitro and in vivo. Deguelin is a rotenoid of the flavonoid family with chemopreventive activities able to decrease tumor incidence in animal models for lung, colon, mammary and skin carcinogenesis through Akt inhibition. Here we show that deguelin belongs to the 'angiopreventive' molecules and provide evidence for molecular events associated with its anti-angiogenic properties. The data show that deguelin inhibits HUVE cells growth by inducing cell-cycle arrest in the G0/G1 phase and in the absence of apoptosis. Growth arrest is associated with induction of p21 and p53 and decreased survivin levels. Deguelin also interferes with several points in the angiogenic process, including inhibition of endothelial cell migration, invasion and metalloprotease production, and potently inhibits in vivo angiogenesis and vascular tumor growth. In addition to Akt, the nuclear factor-kappaB (NF-kappaB) kinase pathway, which plays a critical role in the regulation of inflammation, vascular homeostasis and angiogenesis, was also repressed by deguelin even in the presence of inflammatory stimuli such as tumor necrosis factor-alpha (TNF-alpha). These findings reveal a new therapeutic potential for deguelin in angioprevention and anti-angiogenic therapy.
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PMID:The Akt inhibitor deguelin, is an angiopreventive agent also acting on the NF-kappaB pathway. 1695 9

Cholangiocarcinoma is a highly malignant neoplasm with no effective treatment. Conditionally replicative adenoviruses (CRAds) represent a promising new modality for the treatment of cancer in general. A key contribution in this regard was the introduction of tumor-selective viral replication for amplification of the initial inoculum in the neoplastic cell population. Under ideal conditions following cellular infection, the viruses replicate selectively in the infected tumor cells and kill the cells by cytolysis, leaving normal cells unaffected. However, to date there have been two limitations to the clinical application of these CRAd agents, i.e. poor viral infectivity and tumor specificity. Here we report the construction of three new CRAd agents, CRAd-S.RGD, CRAd-S.F5/3 and CRAd-S.pk7, in which the tumor specificity is regulated by a tumor-specific promoter, the survivin promoter, and the viral infectivity is enhanced by incorporating a capsid modification (RGD, F5/3 or pk7) in the adenovirus fiber region. These CRAd agents effectively target cholangiocarcinoma cells, induce strong cytoxicity in these cells in vitro and inhibit tumor growth in a murine xenograft model in vivo. In addition, the survivin promoter has extremely low activity both in the non-transformed cell line, HMEC, and in human liver tissue. Our results suggest that the survivin-based CRAds are promising agents for targeting cholangiocarcinoma with low host toxicity. Such results should provide important insights into the identification of novel therapeutic strategies for cholangiocarcinoma.
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PMID:Survivin promoter-based conditionally replicative adenoviruses target cholangiocarcinoma. 1701 67

A major goal in cancer gene therapy is to develop efficient gene transfer protocols that allow tissue-specific and tightly regulated expression of therapeutic genes. The ideal vector should efficiently transduce cancer cells with minimal toxicity on normal tissues and persistently express foreign genes. One of the most promising regulatory systems is the mifepristone/RU486-regulated system, which has much lower basal transcriptional activity and high inducibility. In this work, we modified this system by incorporating a cancer-specific promoter, the human telomerase reverse transcriptase (hTERT) promoter. By utilizing hTERT promoter to control the regulator, RU486 could specifically induce the expression of foreign genes in cancer cells but not in normal cells. In the context of this system, a dominant negative mutant of survivin (surDN) was controllably expressed in colorectal tumor cells. The surDN expression induced by RU486 showed a dosage- and time-dependent pattern. Regulated expression of surDN caused caspase-dependent apoptosis in colorectal tumor cells but had little effect on normal cells. Analysis of cell viability showed that RU486-induced expression of surDN suppressed colorectal tumor cell growth and had synergic effect in combination with chemotherapeutic agents. The potential of this system in cancer therapy was evaluated in experimental animals. Tumor xenograft models were established in nude mice with colorectal tumor cells, and RU486 was intraperitoneally administered. The results showed that conditional expression of surDN efficiently inhibited tumor growth in vivo and prolonged the life of tumor-burdened mice. Synergized with the chemotherapeutic drug cisplatin, regulated surDN expression completely suppressed tumor growth. These results indicated that this modified RU486-regulated system could be useful in cancer-targeting therapy.
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PMID:Suppression of colorectal tumor growth by regulated survivin targeting. 1707 82

Survivin, an inhibitor of apoptosis protein, deserves attention as a selective target for cancer therapy because it is overexpressed in many cancers, including human hepatocellular carcinoma (HCC). Here, we report a novel antisense oligonucleotide (ASO) against survivin for its effectiveness against tumor growth both in vitro and in vivo, and providing evidence in treatment for HCC. Initially, transfection of liver tumor cells HepG2 with ASO resulted in significant cells growth inhibition and reduction expression of survivin mRNA and protein, in a dose-dependent manner. Using caspase-3 protease activation assays, we observed that ASO has induced significantly greater apoptosis rate compared to control oligonucleotides. Furthermore, we used an orthotopic transplant model of HCC in nude mice to investigate the effect of ASO on tumor growth in vivo, and ASO reagents were delivered by intravenous injection. Interestingly, this systemic treatment also resulted in significant inhibition in tumor growth. Tumor growth in mice treated with ASO (50 and 75 mg/kg per day) was significantly inhibited (45.31% and 60.94%, respectively) compared with saline-injected group (p < 0.01), in a dose-dependent manner, and the effect of ASO on tumor growth was associated with downregulation of survivin in tumor xenografts. Moreover, the level of serum alpha-fetoprotein in ASO-treated groups was also decreased in a dose-dependent manner. Taken together, these data suggest that the usefulness of survivin ASO could potentially be a promising gene therapy approach to treatment of HCC.
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PMID:Suppression of tumor growth using antisense oligonucleotide against survivin in an orthotopic transplant model of human hepatocellular carcinoma in nude mice. 1715 11

n-3 Polyunsaturated fatty acids have been shown to powerfully inhibit the growth of colon cancer cells, mainly acting as pro-apoptotic agents through inhibition of cycloxygenase-2 (COX-2) expression. Since dysregulation of beta-catenin expression is frequently found at early stage of colorectal carcinogenesis, we analyzed whether docosahexaenoic acid (DHA) may modify the expression of beta-catenin in colon cancer cells (SW480 and HCT116) over-expressing this protein, but lacking COX-2. Futhermore, we investigated if alterations in beta-catenin expression may be associated with apoptosis induction. Treatment of cells with increasing concentrations of DHA induced a dose- and time-dependent inhibition of beta-catenin protein expression which, however, was not accompanied by modifications in beta-catenin transcription. Conversely, the proteasomal inhibitors MG132 and lactacystin prevented DHA-induced beta-catenin decrease, suggesting that DHA may regulate the proteasomal degradation of beta-catenin. The reduced levels of beta-catenin were accompanied by decreased translocation of beta-catenin into the nucleus, where it acts as a transcription factor in concert with T-Cell Factor (TCF). DHA, at the same range of concentrations, was also able to induce apoptosis by a caspase-3-dependent mechanism and to cause a dose- and time-dependent decrease of survivin, an apoptosis inhibitor undetectable in normal tissues and expressed in colorectal cancer through TCF-beta-catenin stimulation. Several other proteins regulated by the TCF-beta-catenin pathway and involved in regulation of tumor growth were down-regulated by DHA, including peroxisome proliferator-activated receptor-delta, membrane type 1 (MT1)-matrix metalloproteinase (MMP), MMP-7 and vascular endothelial growth factor. The present study, thus, raises the possibility that DHA may exert pro-apoptotic and antitumoral effects through proteasomal regulation of beta-catenin levels and alterations in the expression of TCF-beta-catenin target genes.
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PMID:Docosahexaenoic acid induces proteasome-dependent degradation of beta-catenin, down-regulation of survivin and apoptosis in human colorectal cancer cells not expressing COX-2. 1718 61

Survivin is a bifunctional protein that acts as a suppressor of apoptosis and plays a central role in cell division. The protein is strongly expressed in the most common human neoplasms, has prognostic relevance for some of them and appears to be involved in tumor cell resistance to anticancer agents and ionizing radiation. On the basis of these findings, survivin has been proposed as an attractive target for new anticancer interventions. Several preclinical studies have demonstrated that down-regulation of survivin expression or function, accomplished by means of various strategies, reduced tumor growth potential, increased the apoptotic rate and sensitized tumor cells to chemotherapeutic drugs and radiation in different human tumor models. Moreover, the first survivin inhibitors recently entered clinical trials. Recent studies suggest a possible role for survivin in regulating the function of normal adult cells. However, the expression and function of survivin in normal tissues are still not well characterized and understood. Better knowledge of the role of survivin in tumor versus normal cells will be instrumental for the design of optimal strategies to selectively disrupt survivin in cancer.
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PMID:Targeting survivin in cancer therapy: fulfilled promises and open questions. 1734 57


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