UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase (COX)-2, one enzyme isoform responsible for producing prostanoids from arachidonic acid, contributes to colon carcinogenesis. Recently, genetic disruption of COX-1, the other isoform, was shown to decrease the number of intestinal polyps and prostaglandin E(2) levels in intestinal mucosa, like the case with COX-2 gene disruption, in Min mice. We therefore investigated whether a COX-1 selective inhibitor, mofezolac, suppresses intestinal carcinogenesis in rodents. F344 male rats, receiving azoxymethane (AOM, 15 mg/kg body wt) s.c. injections at 5 and 6 weeks of age, were fed a diet containing 600 or 1200 p.p.m. mofezolac for 4 weeks. The number of aberrant crypt foci (ACFs) per rat and the bromodeoxyuridine labeling index of the crypt epithelium were dose-dependently decreased by administration of mofezolac, the value for the former at 1200 p.p.m. being 60% of control value. When Apc gene knockout mice (APC1309 mice) were given 600 or 1200 p.p.m. mofezolac in their diet for 8 weeks, the numbers of intestinal polyps were also dose-dependently decreased, with reduction to 59% of that in the control diet group at the higher dose. Nimesulide, a COX-2 selective inhibitor used as positive control, showed similar suppressive effects on the development of ACFs in AOM-treated rats and polyps in Apc gene knockout mice. The data indicate that both COX-1 and COX-2 can contribute to intestinal tumorigenesis.
Carcinogenesis 2002 Sep
PMID:Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis. 1218 88

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural product occurring in grapes and various other plants with medicinal properties associated with reduced cardiovascular disease and reduced cancer risk. To evaluate the possibility and potential mechanism(s) of which resveratrol inhibits N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis, 96 F344 male rats were divided into 10 groups and resveratrol (1 and 2 mg/kg) was administered orally or intraperitoneally (i.p.). In the groups in which resveratrol was administered at 2 mg/kg (orally, for 16 weeks), 1 and 2 mg/kg (i.p., for 16 weeks) and 1 mg/kg (i.p., for 20 weeks), the number of NMBA-induced esophageal tumors per rat was significantly reduced to 78, 62, 54 and 48, respectively (P < 0.05), and the size of maximum tumors in each group with resveratrol treatment was also significantly smaller than that in NMBA alone group (P < 0.05). Although the pathological examination did not indicate significantly decreased incidence of carcinomas by administering resveratrol, the tendency of carcinogensis suppression was observed (P = 0.177). Semi-quantitative RT-PCR and ELISA analysis demonstrated that following NMBA treatment, the expression of COX-1 mRNA was strongly present in tumor tissues, while weakly present in non-tissues; the expression of COX-2 mRNA was induced in both tumor and non-tumor tissues. The production of prostaglandin E(2) (PGE(2)) increased approximately 6-fold, compared with the normal esophageal mucosa. The higher expression of COX-1, the up-regulated COX-2 expression and the increased levels of PGE(2) synthesis were all significantly decreased by administering resveratrol. Our study suggests that resveratrol suppressed NMBA-induced rat esophageal tumorigenesis by targeting COXs and PGE(2), and therefore may be a promising natural anti-carcinogenesis agent for the prevention and treatment of human esophageal cancer.
Carcinogenesis 2002 Sep
PMID:Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol. 1218 97

Linoleic and alpha-linolenic acids, obtained from plant material in the diet are the precursors in tissues of two families with opposing effects which are referred to as "essential fatty acids" (EFA): arachidonic acid (AA) and pentaene (eicosapentaenoic acid: EPA) and hexaene (docosahexaenoic acid: DHA) acids. The role of EFA is crucial, without a source of AA or compounds which can be converted into AA, synthesis of prostaglandins (PGs) by a cyclooxygenase (COX) enzyme would be compromised, and this would seriously affect many normal metabolic processes. COX, also known as prostaglandin endoperoxide synthase (Pghs) or as prostaglandin G/H synthase, is a key membrane bound enzyme responsible for the oxidation of AA to PGs. Two COX isoforms have been identified, COX-1 and COX-2 that form PGH2, a common precursor for the biosynthesis of thromboxane A2 (TxA2), prostacyclin (PGI2) and PGs (PGD2, PGE2, PGF2alpha. COX-1 enzyme is expressed constitutively in most cells and tissues. Its expression remains constant under either physiological or pathological conditions controlling synthesis of those PGs primarily involved in the regulation of homeostatic functions. In contrast, COX-2 is an intermediate response gene that encodes a 71-kDa protein. COX-2 is normally absent from most cells but highly inducible in certain cells in response to inflammatory stimuli resulting in enhanced PG release. PGs formed by COX-2 primarily mediate pain and inflammation but have multiple effects that can favour tumorigenesis. They are more abundant in cancers than in normal tissues from which the cancers arise. COX-2 is a participant in the pathway of colon carcinogenesis, especially when mutation of the APC (Adenomatous Polyposis Coli) tumour suppressor gene is the initiating event. In addition, COX-2 up-regulation and elevated PGE2 levels are involved in breast carcinogenesis. It seems that there is a correlation between COX-2 level of expression and the size of the tumours and their propensity to invade underlying tissue. Inhibition by non-steroidal anti-inflammatory drugs (NSAIDs) of COX enzymes which significantly suppress PGE2 levels, reduced breast cancer incidence and protected against colorectal cancer. Therefore it is suggested that consumption of a diet enriched in n-3 PUFA (specifically EPA and DHA) and inhibition of COX-2 by NSAIDs may confer cardioprotective effects and provide a significant mechanism for the prevention and treatment of human cancers.
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PMID:Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies. 1219 20

Colorectal cancers (CRCs) are one of the most common forms of cancer in Poland and one of the leading causes of death. The tumors have been attributed to genetic, dietary, and other environmental factors, but recently growth factors such as gastrin have also been implicated in the carcinogenesis. The relationship between plasma amidated and nonamidated gastrin in CRCs is controversial. This study was designed (1) to determine the plasma levels of progastrin and amidated gastrin in 50 CRC patients before and 3-6 months after removal of the tumor, (2) to determine the tumor concentrations of these gastrin peptides and the level of expression for gastrin mRNA and gastrin/CCK(B) receptor mRNA, (3) to examine the expression of cyclooxygenase COX-1 and COX-2 mRNA in CRC tissue, and (4) to compare the prevalence of Hp and its cytotoxic protein, CagA, and cytokines (TNFalpha, IL-1beta, and IL-8) in CRCs, before and after removal of tumor. It was found that the CRC, its resection margin, and the plasma contained severalfold higher levels of progastrin than of amidated gastrins and that the removal of the CRC tumor resulted in a marked reduction in plasma progastrin level without a significant alteration in plasma levels of amidated gastrins. Both gastrin and CCK(B)-R mRNA were detected in the cancer tissue and resection margin by RT-PCR, and similarly, COX-1 and COX-2 mRNA were expressed in these tissues of most CRCs. The seroprevalence of Hp, especially that expressing CagA, and levels of IL-1beta, but not other cytokines, were significantly higher in CRC patients than in 100 age-, gender-, and profession-matched controls and did not change significantly about 3-6 months after tumor resection. We conclude that (1) the CRC and its margin contain large amounts of progastrin and show gene expression of gastrin, CCK(B)-R, and COX-2; (2) removal of the CRC markedly reduces the plasma concentrations of progastrin; (3) the Hp infection rate is higher in CRC, and this may contribute to colorectal cancerogenesis via enhancement of progastrin and gastrin release; and (4) plasma progastrin concentrations might serve as a biomarker of CRC.
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PMID:Progastrin and cyclooxygenase-2 in colorectal cancer. 1235 42

The present study was conducted to assess the inhibitory effects of EGCG (epigallocatechin-3-gallate) on NMBA-induced rat esophageal tumorigenesis and to seek the potential mechanisms. In experiment I, 81 F344 rats were randomly divided into seven experimental groups according to the different regiments of NMBA 1 mg/kg subcutaneously (s.c.) and EGCG 4 mg/kg or 10 mg/kg orally or intraperitoneally (i.p.). The experiment was terminated at 24 weeks. In experiment II, 48 rats were allocated into two groups, each group contained 24 rats, in which the rats were injected with NMBA 1 mg/kg only or a combination of NMBA 1 mg/kg and EGCG 4 mg/kg i.p. Six rats from each group were sacrificed at the 12th, 16th, 20th and 24th week, respectively. The expression of cyclin D1 and cyclooxygenases (COX-2 and COX-1) was detected using semi-quantitative RT-PCR, and the production of prostaglandin E2 (PGE2) was measured by ELISA. In the groups which were treated with EGCG at a dose of 4 mg/kg i.p., or 10 mg/kg both orally and i.p., the mean number of tumors per rat was significantly reduced to 48, 56 and 61%, respectively (p<0.05). The incidence rate of esophageal carcinomas in the rats that were treated with EGCG 4 mg/kg i.p., was significantly lower than that in the rats which only received NMBA 1 mg/kg (p<0.05). The expression of cyclin D1 and COX-2, and the levels of PGE2 were also decreased by EGCG treatment. These results indicated that EGCG significantly inhibits the NMBA-induced rat esophageal carcinogenesis and it inhibitory effects may partly target cyclin D1 and COX-2 expression, and PGE2 production.
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PMID:Inhibitory effects of epigallocatechin-3-gallate on N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in F344 rats. 1242 78

The cyclooxygenase (COX) enzyme system is composed of two isoenzymes, COX-1 and COX-2. Recent sources of experimental and epidemiological evidence suggest a significant role for the COX enzymes, particularly COX-2, in the pathogenesis of breast cancer. This has important implications for treatment of the disease. This article reviews the evidence for a relationship between the COX enzyme system and mammary carcinogenesis, and discusses the likely therapeutic roles and potential pitfalls of COX inhibition.
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PMID:The role of cyclooxygenase-2 (COX-2) in breast cancer, and implications of COX-2 inhibition. 1243 70

It has been found that expression of 15-lipoxygenase-1 (15-LOX-1) and its main product, 13-S-hydroxyoctadecadienoic acid (13-S-HODE), are decreased in human colorectal and esophageal cancers and that non-steroidal anti-inflammatory drugs (NSAIDs) can therapeutically induce 15-LOX-1 expression to trigger apoptosis in those cancer cells. We found that a specific cyclooxygenase-2 (COX-2) inhibitor SC-236 similarly induced apoptosis in gastric cancer cells. In the present study, we tested whether SC-236 induced apoptosis through up-regulation of 15-LOX-1 in gastric cancer. We found that: (i) SC-236 inhibited growth of gastric cancer cells mainly by inducing apoptosis; (ii) SC-236 induced 15-LOX-1 expression and increased endogenous 13-S-HODE product, instead of 15-S-HETE during apoptosis; (iii) SC-236 did not affect expression of COX-1, COX-2, 5-LOX and 12-LOX; and (iv) 15-LOX-1 inhibition suppressed SC-236 induced apoptosis. These findings demonstrated that SC-236 induced apoptosis in gastric cancer cells via up-regulation of 15-LOX-1, and 13-S-HODE. These are potential and new targets for prevention and treatment of gastric cancer.
Carcinogenesis 2003 Feb
PMID:15-Lipoxygenase-1 mediates cyclooxygenase-2 inhibitor-induced apoptosis in gastric cancer. 1258 73

In recent years a dramatic surge has occurred on studies defining to the role of cyclooxygenase (COX)-2 in causation and prevention of cancer. Prostaglandin (PG) endoperoxidase synthase also commonly referred to as COX is a key enzyme involved in the conversion of arachidonic acid to PGs and other eicosanoids. COX exists as two isoforms, namely COX-1 and COX-2 with distinct tissue distribution and physiological functions. COX-1 is constitutively expressed in many tissues and cell types and is involved in normal cellular physiological functions whereas COX-2 is pro-inflammatory in nature and is inducible by mitogens, cytokines, tumor promoters and growth factors. A large volume of data exists showing that COX-2 is overexpressed in a large number of human cancers and cancer cell lines. The possibility of COX-2 as a candidate player in cancer development and progression evolved from the epidemiological studies which suggest that regular use of aspirin or other non-steroidal anti-inflammatory drugs could significantly decrease the risk of developing cancers in experimental animals and in humans. In our recently published study (Prostate, 42 2000 73-78), we provided the first evidence that COX-2 is overexpressed in human prostate adenocarcinoma. Many other studies verified our initial observation and reported that compared to normal tissue, COX-2 is overexpressed in human prostate cancer. It should be noted that some recent work has suggested that COX-2 is only up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. In this scenario, COX-2 inhibitors could afford their effects against prostate carcinogenesis by modulating COX-2 activity in other cells in prostate. An exciting corollary to this ongoing work is that selective COX-2 inhibitors may exhibit chemopreventive and even chemotherapeutic effects against prostate carcinogenesis in humans.
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PMID:Cyclooxygenase-2 and prostate carcinogenesis. 1261 25

The activation of peroxisome proliferator activated receptor gamma (PPARgamma) may play a role in the control of colorectal carcinogenesis. The expression of PPARgamma was examined by Western blotting in human colorectal tumors and matched normal adjacent tissues, as well as in various colorectal carcinoma cell lines. In the tissues, the expression of PPARgamma was elevated in tumors relative to the adjacent normal tissues. Each colorectal carcinoma cell line expressed PPARgamma. The ability of various eicosanoids to bind PPARgamma in colorectal carcinoma cells was investigated using luciferase reporter assays. The well-known PPARgamma ligands, troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J(2) strongly induced PPARgamma binding activity. Products of lipoxygenases displayed moderate binding activity, while other prostaglandins and fatty acids displayed little or no reporter activation. The activation of PPARgamma by 13(S)-HODE, the major metabolite of 15-lipoxygenase-1 from linoleic acid, was concentration dependent reaching maximum at 10 micro M (35-fold activation). The endogenous production of 13(S)-HODE by expression of 15-LO-1 did not activate PPARgamma. The ability of various nonsteroidal anti-inflammatory drugs (NSAIDs) to induce PPARgamma activation was also evaluated. The conventional NSAIDs that inhibit both cyclooxygenases (COX-1 and COX-2) also induced PPARgamma binding activity. In general, however, neither COX-1- nor COX-2-specific inhibitors induced the activation of PPARgamma. Taken together, the metabolites of 15-lipoxygenase and the conventional NSAIDs were confirmed as exogenous ligands for PPARgamma in colorectal carcinoma cells.
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PMID:Evaluation of eicosanoids and NSAIDs as PPARgamma ligands in colorectal carcinoma cells. 1271 Dec 49

The role of nitric oxide (NO) in colon cancer remains controversial. Inducible nitric oxide synthase (iNOS) has been reported to be up regulated and down regulated in colorectal cancer in both animal models and patient tissue samples. Cyclooxygenase-2 (COX-2) is important in colorectal carcinogenesis but its relationship with NO has never been studied in colon cancer. Three colon cancer cell lines (HCA7, HT29 and HCT116) with different COX-2 expression and activities were used to study the effect of the NO donor, S-nitrosoglutathione (GSNO). The effects of GSNO (10-500 micro M) on cell growth, PGE(2) production, COX-1/COX-2 protein expression and cell-cycle distribution were evaluated. GSNO increased PGE(2) production and induced COX-1 and COX-2 protein expression in a dose- and time-dependent manner. Higher concentrations of GSNO also inhibited cell growth and induced apoptosis in all three cell lines, regardless of their COX-2 expression/activities. Inhibition of PGE(2) production did not further improve the inhibitory effect of GSNO.
Carcinogenesis 2003 Apr
PMID:Nitric oxide induces cyclooxygenase expression and inhibits cell growth in colon cancer cell lines. 1272 90

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