Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase-2 (COX-2) is the inducible isoform of the rate-limiting enzymes that convert arachidonic acid to proinflammatory prostaglandins as well as a primary target for nonsteroidal anti-inflammatory drugs. Accumulating evidence suggests that up-regulation of COX-2 is associated with carcinogenesis in multiple organ systems including the large bowel, lung, breast, and prostate. In this report, we examine the expression of COX-2 protein and mRNA in prostate tissue containing various lesions and in prostate cancer cell lines. In the cell lines, LNCaP, DU145, PC-3, and TSU, COX-2 protein expression was undetectable under basal conditions but could be induced transiently by phorbol ester treatment in PC-3 and TSU cells, but not in DU145 and LNCaP cells. Immunohistochemical analysis of 144 human prostate cancer cases suggested that, in contrast to several previous reports, there was no consistent overexpression of COX-2 in established prostate cancer or high-grade prostatic intraepithelial neoplasia, as compared with adjacent normal prostate tissue. Positive staining was seen only in scattered cells (<1%) in both tumor and normal tissue regions but was much more consistently observed in areas of proliferative inflammatory atrophy, lesions that have been implicated in prostatic carcinogenesis. Staining was also seen at times in macrophages. Western blotting and quantitative RT-PCR analyses confirmed these patterns of expression. These results suggest that if nonsteroidal anti-inflammatory drugs are indeed chemopreventive and/or chemotherapeutic for prostate cancer, their effects are likely to be mediated by modulating COX-2 activity in non-PCa cells (either inflammatory cells or atrophic epithelial cells) or by affecting a COX-2-independent pathway.
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PMID:Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. 1175 73

Pharmacologically safe compounds that can inhibit the proliferation of tumor cells have potential as anticancer agents. Curcumin, a diferuloylmethane, is a major active component of the food flavor turmeric (Curcuma longa) that has been shown to inhibit the proliferation of a wide variety of tumor cells. The apoptotic intermediates through which curcumin exhibits its cytotoxic effects against tumor cells are not known, and the participation of antiapoptotic proteins Bcl-2 or Bcl-xl in the curcumin-induced apoptosis pathway is not established. In the present report we investigated the effect of curcumin on the activation of the apoptotic pathway in human acute myelogenous leukemia HL-60 cells and in established stable cell lines expressing Bcl-2 and Bcl-xl. Curcumin inhibited the growth of HL-60 cells (neo) in a dose- and time-dependent manner, whereas Bcl-2 and Bcl-xl-transfected cells were relatively resistant. Curcumin activated caspase-8 and caspase-3 in HL-60 neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Similarly, time-dependent poly(ADP)ribose polymerase (PARP) cleavage by curcumin was observed in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Curcumin treatment also induced BID cleavage and mitochondrial cytochrome c release in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. In neo HL-60 cells, curcumin also downregulated the expression of cyclooxygenase-2. Because DN-FLICE blocked curcumin-induced apoptosis, caspase-8 must play a critical role. Overall, our results indicate that curcumin induces apoptosis through mitochondrial pathway involving caspase-8, BID cleavage, cytochrome c release, and caspase-3 activation. Our results also suggest that Bcl-2 and Bcl-xl are critical negative regulators of curcumin-induced apoptosis.
Carcinogenesis 2002 Jan
PMID:Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. 1175 35

Accumulating evidence indicates that overproduction of prostanoids attributable to overexpression of cyclooxygenase-2 (COX-2) plays an important role in colon carcinogenesis. We have shown recently that the prostaglandin (PG) E receptor, EP(1), but not EP(3), is involved in mouse colon carcinogenesis. In line with our previous study, here we examined the role of prostanoid receptors in colon carcinogenesis using six additional lines of knockout mice deficient in prostanoid receptors EP(2), EP(4), DP, FP, IP, or TP. The animals were treated with the colon carcinogen, azoxymethane (AOM), and examined for the development of aberrant crypt foci (ACFs), putative preneoplastic lesions in the colon. Formation of ACFs was decreased only in the EP(4)-knockout mice, to 56% of the wild-type level. To confirm these results, we also examined the inhibitory effects of an EP(4)-selective antagonist, ONO-AE2-227, in the diet on the formation of AOM-induced colon ACFs in C57BL/6Cr mice and on the development of intestinal polyps in Min mice. ONO-AE2-227 at a dose of 400 ppm reduced the formation of ACFs to 67% of the control level, and intestinal polyp numbers in Min mice receiving 300 ppm were decreased to 69% of the control level. Plating efficiency assays showed that addition of 1.0 microM ONO-AE1-329, an EP(4)-selective agonist, resulted in a 1.8-fold increase in the colony number of the human colon cancer cell line, HCA-7, similar to the effect of PGE(2). Moreover, EP(4) mRNA expression was clearly observed in normal colon mucosa and colon tumors in mice. Our previous and present results indicate that PGE(2) contributes to colon carcinogenesis through its actions mediated through EP(1) and EP(4) receptors; therefore, antagonists for these two receptors may be good candidates as chemopreventive agents against colon cancer.
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PMID:Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. 1178 53

Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2), an inducible form of COX, represents a potential pharmacologic target to prevent cancer. Key data suggesting a causal relationship between increased COX-2 activity and carcinogenesis and possible mechanisms of action of COX-2 in this context will be discussed. The possibility that COX-2 represents a pharmacological target for preventing upper aerodigestive cancers (head and neck, lung) will be emphasized. Importantly, clinical trials have been initiated to assess the chemopreventive properties of selective COX-2 inhibitors.
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PMID:Inhibition of cyclooxygenase-2: an approach to preventing cancer of the upper aerodigestive tract. 1179 29

Butyrate suppresses the growth of colon cancer cells, inducing differentiation and apoptosis in vitro. Increased expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) has been suggested to be closely involved in colon carcinogenesis. In this study, effects of sodium butyrate on the promoter-dependent transcriptional activity of iNOS and COX-2 genes were investigated in a colon cancer cell line, DLD-1, using a reporter gene assay system. Sodium butyrate significantly reduced promoter-dependent iNOS transcriptional activity dose-dependently at concentrations higher than 0.1 mM. COX-2 transcriptional activity was not suppressed, but slightly increased. While hyperacetylated histones appeared at concentrations of sodium butyrate suppressing iNOS gene promoter activity, promoter-dependent transcriptional activities of iNOS and COX-2 genes were both increased by the histone deacetylase inhibitor trichostatin A. These results suggested that sodium butyrate exhibits differential effects on iNOS and COX-2 genes, acting to suppress iNOS expression via mechanisms independent of histone acetylation.
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PMID:Suppression of promoter-dependent transcriptional activity of inducible nitric oxide synthase by sodium butyrate in colon cancer cells. 1182 62

Increased expression of cyclooxygenase-2 (COX-2) significantly enhances carcinogenesis and inflammatory reactions. Regulation of COX-2 overexpression may be a reasonable target for cancer chemoprevention. We have tested the hypothesis that levels of COX-2 expression determine the growth of human lung cancer cells in nude mice. Two cell lines, NCI-H460 (non-small cell lung cancer) and NCI-H69 (small cell lung cancer) were selected because the former expresses high levels of COX-2 protein and the latter has no detectable levels. We also examined the effects of 1,4-phenylenebis(methylene)selenocyanate (p-XSC), a highly effective chemopreventive organoselenium compound and known inhibitor of COX-2 expression, in vivo, on cell growth and COX-2 expression in vitro in the NCI-H460 cancer cell line. Cells were exposed to p-XSC at levels between 10 and 100 microM for six days and showed toxicity at approximately 50 microM. Pre-exposure of NCI-H460 to non-toxic levels of p-XSC suppressed COX-2 protein expression in a dose-dependent manner. At 40 microM, p-XSC suppressed phorbol myristate acetate (PMA)-induced COX-2 expression in NCI-H460 cells by more than 66%. In vivo studies in athymic mice showed a significant difference in tumor volume between cell lines. Pre-treatment of NCI-H460 cells with a non-toxic dose of p-XSC, prior to their injection into nude mice, significantly suppressed tumor growth when compared to untreated cells. Collectively, the outcome of our in vitro and in vivo studies supports the hypothesis that levels of COX-2 expression determine the extent of human lung tumor growth in athymic mice. Therefore, inhibition of COX-2 expression by agents such as p-XSC provides a strong rationale for the development of future clinical prevention trials.
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PMID:Cyclooxygenase-2 expression influences the growth of human large and small cell lung carcinoma lines in athymic mice: impact of an organoselenium compound on growth regulation. 1183 68

Cyclooxygenase-2 (COX-2) is the inducible isoform of cyclooxygenase, the enzyme that catalyzes the rate-limiting step in prostaglandin synthesis from arachidonic acid. Various prostaglandins are produced in a cell type-specific manner, and they elicit cellular functions via signaling through G-protein coupled membrane receptors, and in some cases, through the nuclear receptor PPAR. COX-2 utilization of arachidonic acid also perturbs the level of intracellular free arachidonic acid and subsequently affects cellular functions. In a number of cell and animal models, induction of COX-2 has been shown to promote cell growth, inhibit apoptosis and enhance cell motility and adhesion. The mechanisms behind these multiple actions of COX-2 are largely unknown. Compelling evidence from genetic and clinical studies indicates that COX-2 upregulation is a key step in carcinogenesis. Overexpression of COX-2 is sufficient to cause tumorigenesis in animal models and inhibition of the COX-2 pathway results in reduction in tumor incidence and progression. Therefore, the potential for application of non-steroidal anti-inflammatory drugs as well as the recently developed COX-2 specific inhibitors in cancer clinical practice has drawn tremendous attention in the past few years. Inhibition of COX-2 promises to be an effective approach in the prevention and treatment of cancer, especially colorectal cancer.
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PMID:Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. 1185 43

We have reported previously [Bauer,A.K. et al. (2001) Exp. Lung Res., 27, 197-216] that the 13 CXB recombinant inbred mouse strains derived from BALB/cByJ and C57BL/6J progenitors vary in their responsiveness to both lung tumor promotion and pulmonary inflammation induced by chronic administration of butylated hydroxytoluene (BHT). Herein we have applied these data, along with markers known to be polymorphic among these strains, to conduct linkage analysis of these susceptibilities. This enabled us to assign provisional quantitative trait loci (QTL) that govern these strain variations in susceptibility as a genetic approach to assessing the influence of inflammation on tumorigenesis. A Chr 15 (39.1-55.6 cM) QTL regulated susceptibility to two-stage carcinogenesis, a protocol in which chronic BHT exposure followed a single urethane injection; a similar QTL on Chr 15 (46.7-61.7 cM) influenced BHT induction of cyclooxygenase-2 (COX-2) expression. A Chr 18 (37-41 cM) QTL modulated both the number of lung tumors induced by 3-methylcholanthrene (MCA) injection with subsequent treatment with BHT as well as BHT-induced ingress of macrophages into airways. Other chromosomal sites that affected either the degree of BHT-elicited macrophage infiltration, Chr 9 (48-61 cM), or COX-2 induction, Chr 10 (59-65 cM), were reported to influence susceptibility to lung tumorigenesis in other strains. The fact that common chromosomal locations regulate both inflammation and carcinogenesis suggests a pathogenic role of inflammatory mediators in tumor development that may be exploited for chemoprevention of lung cancer.
Carcinogenesis 2002 Mar
PMID:Quantitative trait locus mapping of susceptibilities to butylated hydroxytoluene-induced lung tumor promotion and pulmonary inflammation in CXB mice. 1189 55

Although the results of clinical intervention trials of beta-carotene to prevent lung cancer, and of dietary augmentation with fibre or fruit and vegetables to reduce the occurrence of colonic polyps have so far been negative, a structured path for the development of diet-derived constituents as cancer chemopreventive agents is emerging. Putative agents are identified on the basis of epidemiological and preclinical mechanistic studies. Some examples of promising diet-derived chemopreventive agents are folate, curcumin, genistein, and tea catechins. Long-term supplementation of the diet with folate seems to lower the risk of colorectal cancer. Curcumin in the spice turmeric, genistein in soya, and catechins in tea have tumour-suppressing properties in rodent models of carcinogenesis, and they interfere with cellular processes involved in tumour promotion and progression. Kinases, telomerase, cyclooxygenase-2, triggers of apoptosis, and transcription factors AP1 and nuclear factor kappaB are among the cellular targets. The investigation of dietary constituents should follow a structured design, incorporating parallel preclinical studies of the food source and the isolated agent in terms of efficacy, toxicity, biological mechanisms, and pharmacokinetics. Either the food source or the isolated agent should be selected for further development on the basis of dose-efficacy and toxicity data. Pilot clinical trials on the pharmacokinetics and mechanism-based markers of efficacy of the selected intervention should precede phase I-III development in suitable populations.
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PMID:Cancer chemoprevention by dietary constituents: a tale of failure and promise. 1190 54

Epidemiological, experimental, and clinical studies have demonstrated that colon carcinogenesis may be prevented by nonsteroidal anti-inflammatory drugs (NSAIDs). Although controversy remains, recent studies, including ours, have revealed that NSAIDs suppress colon carcinogenesis at the adenoma stage where cyclooxygenase-2 (COX-2), a major molecular target in this action, is mainly expressed in interstitial cells but not in tumour cells. Therefore, it is unlikely that NSAIDs prevent colon cancer formation through modulating the functions of tumour cells. A more possible assumption is that NSAIDs suppress colon carcinogenesis through the inhibition of prostaglandin formation. However, the mechanisms by which prostanoids promote colon carcinogenesis have not been elucidated to date. A prostanoids act through both membrane receptors and nuclear receptors such as peroxisome proliferator receptor (PPAR) gamma or delta, one focus in this area is to investigate their roles in colon carcinogenesis, including the induction of growth factors.
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PMID:Review article: COX-2, prostanoids and colon cancer. 1196 30


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