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)

We examined the effect of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, and N-(9-fluorenyl-methyloxycarbonyl)-L-leucine (F-L-Leu), a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, separately and combined, on the development of methylnitrosourea (MNU)-induced rat mammary gland carcinogenesis. Celecoxib and F-L-Leu significantly reduced tumor incidence and multiplicity (P < 0.05). Combining both agents exerted higher (synergistic) cancer inhibition than separate treatments (P < 0.05). The effects of the test drugs on COX-2 and PPAR gamma expression and on the synthesis of prostaglandin E(2) (PGE(2)) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) were examined in rat mammary normal (MNU-untreated), uninvolved, and tumor (MNU-treated) tissues. Celecoxib and F-L-Leu, separately, inhibited COX-2 and up-regulated PPAR gamma expression. These effects were paralleled by inhibition of PGE(2) synthesis and up-regulation of 15d-PGJ(2). Combined treatment resulted in higher alterations in COX-2 and PPAR gamma transcripts and PG synthesis compared with separate administrations. The effect of the test agents on Bcl(2), BAX, and protein kinase C alpha expression levels were examined in the rat mammary gland and the pro-(BAX:Bcl(2)) and anti-[PKC alpha*(Bcl(2)/BAX)] apoptotic ratios were evaluated. Each drug increased the proapoptotic ratio by 2- to 7-fold and reduced the antiapoptotic ratio by 2- to >8-fold in all tissues. Combined treatment, however, resulted in >9- to 14-fold up-regulation in the proapoptotic processes and 15- to >30-fold down-regulation in the antiapoptotic ones. Analyses were also carried out on the drug-induced modulation of cell cycle regulators and proliferation markers (cyclin-dependent kinase 1 and proliferating cell nuclear antigen). F-L-Leu and celecoxib each reduced the cyclin-dependent kinase 1 and proliferating cell nuclear antigen expression in the tumor. Higher down-regulation was attained in all tissues by combined treatment where cyclin-dependent kinase 1 and proliferating cell nuclear antigen almost retained the expression levels observed in the normal glands. In conclusion, simultaneous targeting of COX-2 and PPAR gamma may inhibit mammary cancer development more effectively than targeting each molecule alone. COX-2 inhibitors and PPAR gamma agonists coordinately mediate their anticancer effect via both COX-dependent (inhibition of COX-2, activation of PPAR gamma, and modulation PG synthesis) and COX-independent (induction of proapoptotic factors and inhibition of cell proliferation) pathways.
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PMID:Inhibition of rat mammary gland carcinogenesis by simultaneous targeting of cyclooxygenase-2 and peroxisome proliferator-activated receptor gamma. 1615 91

Several epidemiological, clinical and experimental studies established nonsteroidal anti-inflammatory drugs (NSAIDs) as promising cancer chemopreventive agents. Long-term use of aspirin and other NSAIDs has been shown to reduce the risk of cancer of the colon and other gastrointestinal organs as well as of cancer of the breast, prostate, lung, and skin. Understanding the action of NSAIDs provides substantial insights into the mechanisms by which these unique agents regulate tumor cell growth and enable better strategies for prevention and treatment. NSAIDs restore normal apoptosis and reduce cell proliferation in human adenomatous colorectal polyps, experimental colonic tumors, and in various cancer cell lines that have lost critical genes required for normal function. NSAIDs, particularly selective cyclooxygenase-2 (COX-2) inhibitors such as celecoxib, have been shown to inhibit angiogenesis in cell culture and in rodent models of angiogenesis. Exploration of the multistep process of carcinogenesis has provided substantial insights into the mechanisms by which NSAIDs modulate these events. However, unresolved questions with regard to safety, efficacy, optimal treatment regimen, and mechanism of action currently limit the clinical application of NSAIDs to the prevention of polyposis in FAP patients. Moreover, the development of safe and effective NSAIDs for chemoprevention is complicated by the potential that rare, serious toxicity may offset the benefit of treatment with these drugs given to healthy individuals who have a low risk of developing the disease. Growing knowledge in this area has brought about innovative approaches using combine actions of NSAIDs with other agents that have different modes of action. It has also led to the development of nitric oxide-releasing NSAIDs, that induce tumor cell apoptosis and compensate for COX function, as a means of increasing efficacy and minimizing toxicity. There is growing optimism for the view that full exploration of the role of NSAIDs in the prevention and treatment of epithelial cancers will serve towards reducing of mortality and morbidity from various cancers.
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PMID:NSAIDs and chemoprevention. 1496 65

Epidemiological studies have noted a consistent association between the consumption of diets rich in fruits and vegetables and a lower risk for chronic diseases including cancer and cardiovascular disease. There is accumulating evidence that much of the health-promoting potential of these plant foods may come from phytochemicals, bioactive compounds not designated as traditional nutrients. In strawberries, the most abundant of these are ellagic acid, and certain flavonoids: anthocyanin, catechin, quercetin and kaempferol. These compounds in strawberries have potent antioxidant power. Antioxidants help lower risk of cardiovascular events by inhibition of LDL-cholesterol oxidation, promotion of plaque stability, improved vascular endothelial function, and decreased tendency for thrombosis. Furthermore, strawberry extracts have been shown to inhibit COX enzymes in vitro, which would modulate the inflammatory process. Individual compounds in strawberries have demonstrated anticancer activity in several different experimental systems, blocking initiation of carcinogenesis, and suppressing progression and proliferation of tumors. Preliminary animal studies have indicated that diets rich in strawberries may also have the potential to provide benefits to the aging brain.
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PMID:Potential impact of strawberries on human health: a review of the science. 1507 79

Emerging reports now implicate alterations of arachidonic acid (AA) metabolism with prostate carcinogenesis. To test this hypothesis, androgen-primed benign hyperplastic (BHC) and malignant tumorigenic (MTC) cells derived from the Lobund-Wistar rat model of autochthonous prostate adenocarcinoma were incubated with (14)C-AA. Our data using MTCs revealed enhanced dual metabolism of (14)C-AA via COX to generate increased PGE(2) and via 5-lipoxygenase (LOX) to generate increased 5S-HETE in tumorigenic cells. Western blot of MTCs revealed upregulation of COX-2 expression. This paralleled the increased biosynthesis of PGE(2). Since some polyunsaturated fatty acids have been reported to modulate AA metabolism and tumorigenesis, we primed the cells with either gamma-linolenic acid (GLA) or its in vivo metabolite, 15S-HETrE, prior to incubation with AA. Our data revealed suppression of COX-2 expression/PGE(2) biosynthesis. In parallel, priming cells with 15S-HETrE resulted in greater suppression of COX-2 expression/PGE(2) biosynthesis. These findings suggest that 15S-HETrE could function in vivo after dietary intake of GLA to suppress DHT-enhanced prostatic COX-2 expression/PGE(2) biosynthesis and, thus, alleviate tumor growth and progression.
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PMID:Suppression of cyclooxygenase-2 overexpression by 15S-hydroxyeicosatrienoic acid in androgen-dependent prostatic adenocarcinoma cells. 1519 70

n-3 Polyunsaturated fatty acids (PUFAs) inhibit the development of microvessels in mammary tumors growing in mice. Human colorectal tumors produce vascular endothelial growth factor (VEGF) whose expression is up-regulated in tumor cells by both cyclooxygenase-2 (COX-2) and PGE(2) and directly correlated to neoangiogenesis and clinical outcome. The goal of this study was to examine the capability of n-3 PUFAs to regulate VEGF expression in HT-29 human colorectal cells in vitro and in vivo. Constitutive VEGF expression was augmented in cultured HT-29 cells by serum starvation and the effects of eicosapentaenoic (EPA) or docosahexaenoic acid (DHA) on VEGF, COX-2, phosphorylated extracellular signal-regulated kinase (ERK)-1 and -2 and hypoxia-inducible-factor 1-alpha (HIF-1alpha) expression and PGE(2) levels were assessed. Tumor growth, VEGF, COX and PGE(2) analysis were carried out in tumors derived from HT-29 cells transplanted in nude mice fed with either EPA or DHA. Both EPA and DHA reduced VEGF and COX-2 expression and PGE(2) levels in HT-29 cells cultured in vitro. Moreover, they inhibited ERK-1 and -2 phosphorylation and HIF-1alpha protein over-expression, critical steps in the PGE(2)-induced signaling pathway leading to the augmented expression of VEGF in colon cancer cells. EPA always showed higher efficacy than DHA in vitro. Both fatty acids decreased the growth of the tumors obtained by inoculating HT-29 cells in nude mice, microvessel formation and the levels of VEGF, COX-2 and PGE(2) in tumors. The data provide evidence that these n-3 PUFAs are able to inhibit VEGF expression in colon cancer cells and suggest that one possible mechanism involved may be the negative regulation of the COX-2/PGE(2) pathway. Their potential clinical application as anti-angiogenic compounds in colon cancer therapy is proposed.
Carcinogenesis 2004 Dec
PMID:n-3 PUFAs reduce VEGF expression in human colon cancer cells modulating the COX-2/PGE2 induced ERK-1 and -2 and HIF-1alpha induction pathway. 1535 33

The aim of this study was to determine the macrophage migration inhibitory factor (MIF) protein and mRNA expression in esophageal squamous cell carcinoma (ESCC), and the effect of bile acids, aspirin and a selective cyclooxygenase-2 (COX-2) inhibitor, NS398, on MIF expression in ESCC cells in vitro. Specimens from tumors and the adjacent non-cancerous tissues were obtained from 52 ESCC patients. Western blotting was used for the detection of MIF protein expression, and reverse transcription-polymerase chain reaction (RT-PCR) for MIF mRNA expression. Cells of an ESCC cell line, Eca-109, were treated with chenodeoxycholate (CD, 100 mM), glycochenodeoxycholate (GCD, 1 mM), aspirin (1 mM) or NS398 (1 microM). Enzyme-linked immunosorbent assay (ELISA) and RT-PCR were used to detect the expression of the MIF protein and mRNA, respectively, in the supernatant and cultured cells. Western blotting demonstrated that levels of MIF protein were increased in tumors versus non-malignant tissues, with the expression ratio of MIF over beta-actin of 0.93 +/- 0.21 and 0.57 +/- 0.08, respectively (P = 0.012). In vitro, both CD and GCD induced a dramatic increase in MIF protein and mRNA in ESCC cells. On the other hand, aspirin and NS398 significantly decreased MIF protein and mRNA expression, and completely blocked bile acid-induced MIF synthesis in the presence or absence of prostaglandin E(2). In conclusion, MIF expression is increased in ESCC. Whereas bile acids induce MIF expression in ESCC cells, aspirin and NS398 significantly inhibit MIF expression, even in the presence of bile acids, via a COX-independent mechanism.
Carcinogenesis 2005 Jan
PMID:Expression of macrophage migration inhibitory factor in esophageal squamous cell carcinoma and effects of bile acids and NSAIDs. 1535 35

Fatty acid hydroperoxides arise from unsaturated fatty acids in the presence of oxygen and elevated temperature during processing of food. Here we have studied their effects on gene expression in colorectal tumor cells using linoleic acid hydroperoxide (LOOH) as a model compound. Its addition to the medium of LT97 human adenoma cells and SW480 human carcinoma cells enhanced the production of intracellular hydrogen peroxide. Furthermore, in both cell lines, increases in VEGF mRNA and protein were observed. Unoxidized linoleic acid had little or no activity. Concomitantly, COX-2 expression was up-regulated. In the LT97 cells, the COX inhibitors SC58560 and SC58236 completely prevented the VEGF induction, suggesting that the effect was dependent on prostaglandin synthesis. In vivo prostaglandin-mediated induction of VEGF secretion is known to be essential for the growth of adenomatous polyps and their progression to carcinomas. Therefore, our results for the first time implicate dietary lipid hydroperoxide as a key risk factor in colon carcinogenesis.
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PMID:Dietary lipid hydroperoxides induce expression of vascular endothelial growth factor (VEGF) in human colorectal tumor cells. 1552 6

Epithelial ovarian neoplasms can be divided into two major categories on the basis of their pathological and clinical behaviors: invasive ovarian tumors and borderline ovarian tumors. However, neither the etiology nor the pathogenesis of the borderline and invasive epithelial ovarian carcinomas has been understood completely. Borderline tumors are clearly more favaroble in terms of survival. The same pathological types can be seen both in borderline and invasive tumors. However; it is not clear if both diseases is a continuum of the same entity or are independent clinical entities. On the other hand, several in vivo and in vitro studies have demonstrated that overexpression of the cyclooxygenase-2 (COX-2) may have an important role in the development and the aggressive clinical behaviors of different malignancies. Furthermore, some recent studies have also revealed the overexpression of COX-2 in invasive epithelial ovarian carcinomas. In this manuscript, we propose that lower expressions of COX-2 may have a role in the development of borderline ovarian neoplasias, whereas higher levels have a role in the invasive epithelial ovarian cancers and this may be the basis for the clinical difference of both entities. To test this hypothesis; genetic, pathologic and epidemiologic studies may be performed. Patients with borderline tumors should be compared with the invasive counterparts in terms of COX mutations and expressions. Also, epidemiologic studies may reveal the role of COX inhibitors in the ovarian carcinogenesis. If this hypothesis is proven to be true, this may direct the clinicians to use prophylactic NSAIDs with or without combined oral contraceptives especially in high risk patients. Also, this hypothesis may enlight a new gene therapy targeting COX-2 gene in high risk patients for the development of EOC.
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PMID:Lower expression of cyclooxygenase-2: is it associated with the development of borderline ovarian tumors? 1560 54

The presence of prostaglandins (PGs) has been demonstrated in the processes of carcinogenesis and inflammation. In the present study, we found that 12-o-tetradecanoylphorbol 13-acetate (TPA) induced cyclooxygenase 2 (COX-2), but not COX-1, protein expression in HL-60 cells, and the addition of arachidonic acid (AA) in the presence or absence of TPA significantly reduced the viability of HL-60 cells, an effect that was blocked by adding the COX inhibitors, NS398 and aspirin. The AA metabolites, PGD(2) and PGJ(2), but not PGE(2) or PGF(2alpha), reduced the viability of the human HL60 and Jurkat leukemia cells according to the MTT assay and LDH release assay. Apoptotic characteristics including DNA fragmentation, apoptotic bodies, and hypodiploid cells were observed in PGD(2)- and PGJ(2)-treated leukemia cells. A dose- and time-dependent induction of caspase 3 protein procession, and PARP and D4-GDI protein cleavage with activation of caspase 3, but not caspase 1, enzyme activity was detected in HL-60 cells treated with PGD(2) or PGJ(2). Additionally, DNA ladders induced by PGD(2) and PGJ(2) were significantly inhibited by the caspase 3 peptidyl inhibitor, Ac-DEVD-FMK, but not by the caspase 1 peptidyl inhibitor, Ac-YVAD-FMK, in accordance with the blocking of caspase 3, PARP, and D4-GDI protein procession. An increase in intracellular peroxide levels by PGD(2) and PGJ(2) was identified by the DCHF-DA assay, and anti-oxidant N-acetyl cysteine (NAC), mannitol (MAN), and tiron significantly inhibited cell death induced by PGD(2) and PGJ(2) by reducing reactive oxygen species (ROS) production. The PGJ(2) metabolites, 15-deoxy-Delta(12,14)-PGJ(2) and Delta(12)-PGJ(2), exhibited effective apoptosis-inducing activity in HL-60 cells through ROS production via activation of the caspase 3 cascade. The proliferator-activated receptor-gamma (PPAR-gamma) agonists, rosiglitazone (RO), troglitazone (TR), and ciglitazone (CI), induced apoptosis in cells which was blocked by the addition of the PPAR-gamma antagonists, GW9662 and BADGE, via blocking of caspase 3 and PARP cleavage. However, neither GW9662 nor BADGE showed any protective effect on PGD(2)- and PGJ(2)-induced apoptosis. A differential apoptotic effect of PGs through ROS production, followed by activation of the caspase 3 cascade, was demonstrated.
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PMID:Prostaglandin D(2) and J(2) induce apoptosis in human leukemia cells via activation of the caspase 3 cascade and production of reactive oxygen species. 1584 42

There is now substantial evidence for a role for cyclooxygenase-2 (COX-2)-mediated prostaglandin (PG) signalling during carcinogenesis in a number of tissues and selective COX-2 inhibitors (coxibs) were considered attractive candidate chemoprevention agents. However, recent concerns over the toxicity of systemic selective COX-2 inhibition and the realisation that COX-1 may also contribute to carcinogenesis have cast some doubt on COX-2 inhibition as a safe and effective chemoprevention strategy. This review will describe the available evidence relating to the known benefits (preventive efficacy in rodent tumorigenesis models and limited human data from small randomised, controlled trials and epidemiological studies) and risks (cardiovascular and renal toxicity) of coxib therapy for cancer chemoprevention. Potential, alternative strategies for inhibition of COX-PG signalling that minimise or avoid systemic selective COX-2 inhibition will also be discussed.
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PMID:Cyclooxygenase-2: how good is it as a target for cancer chemoprevention? 1600 78


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