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 overexpressed in various types of human malignancies including squamous cell carcinomas (SCCs) of the esophagus, but little is known about COX-2 expression in premalignant esophageal squamous dysplasia. To elucidate the role of COX-2 in esophageal carcinogenesis, we examined the expression of this enzyme in normal squamous epithelium (n = 42), squamous dysplasia [high-grade dysplasia (HGD, n = 41; low-grade dysplasia (LGD, n = 33)]; carcinoma in situ (n = 16), mucosal invasive carcinoma (n = 18), and advanced SCC (n = 45). Immunohistochemistry showed a significantly high COX-2 expression in HGD compared with other lesions. The COX-2 score, an index determined by intensity and positivity of COX-2 staining (maximum 3.0), was 0.29 +/- 0.04 in normal esophagus, 1.75 +/- 0.11 in LGD, 2.89 +/- 0.05 in HGD, 2.17 +/-0.18 in CIS, 1.95 +/- 0.22 in mucosal invasive carcinoma, and 1.81 +/- 0.08 in advanced SCC. Results of reverse transcription-PCR assays confirmed those obtained by immunohistochemistry. COX-2 expression correlated with proliferation activity assessed by the proliferating cell nuclear antigen index in dysplastic lesions (P = 0.001) but not in SCCs. COX-2 expression in SCC did not correlate with various clinicopathological parameters including prognosis. Our results indicate that COX-2 is a sensitive marker for HGD and suggest that COX-2 may be involved in early stages of squamous carcinogenesis of the esophagus.
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PMID:Up-regulation of cyclooxygenase-2 in squamous carcinogenesis of the esophagus. 1077 45

Mutations of the adenomatous polyposis coli gene (Apc) have been implicated in the occurrence of sporadic colon cancer. Various Apc knockout strains of mice have been created to better understand the function of this gene. In the present study, using gene targeting, we disrupted the mouse Apc gene at the end of exon 10 to compare its effect with the effects of other types of Apc gene disruption, all of which are on exon 15. The mice expressed a mutant form of mRNA that encoded 474 amino acids instead of 2845 amino acids due to exon duplication. In addition, these Apc(Delta474) knockout mice developed intestinal and mammary tumors. Since the most severe cases of familial adenomatous polyposis are associated with mutations on exon 15, our mutation at exon 10 was expected to result in a mild phenotype. However, the number of polyps that our mice developed was similar to that of other Apc knockout mice such as Apc(Min) and Apc(1309) mice. Cyclooxygenase-2 (COX-2) has been implicated in colorectal carcinoma. Apc(Delta474) mice treated with JTE-522, a novel COX-2-selective inhibitor, showed a significantly reduced number of polyps. These results suggest that COX-2 plays an important role in polypogenesis and COX-2-selective inhibitors can be used as new preventive therapeutics against colorectal tumors.
Carcinogenesis 2000 May
PMID:Suppression of polypogenesis in a new mouse strain with a truncated Apc(Delta474) by a novel COX-2 inhibitor, JTE-522. 1078 17

Cyclooxygenase-2 (COX-2) is abundantly expressed in colon cancer cells. It has been reported that inhibition of COX-2 enzyme activity is shown to prevent colon carcinogenesis. Thus, suppression of COX-2 expression may also be an effective chemopreventive strategy. In the present study, we constructed a beta-galactosidase reporter gene system in human colon cancer DLD-1 cells, and measured COX-2 promoter-dependent transcriptional activity in the cells. Interferon gamma suppressed this COX-2 promoter activity, while 12-O-tetradecanoylphorbol-13-acetate and transforming growth factor alpha (TGFalpha) exerted enhancing effects. We then tested the influence of 14 candidate cancer chemopreventive compounds on COX-2 promoter activity. Chemopreventive agents such as quercetin, kaempferol, genistein, resveratrol and resorcinol, all having a common resorcin moiety, were found to effectively suppress the COX-2 promoter activity with and without TGFalpha-stimulation in DLD-1 cells. Since all these compounds have a resorcin moiety as a common structure, a resorcin-type structure may play an active role in the inhibition of COX-2 expression in colon cancer cells.
Carcinogenesis 2000 May
PMID:Suppression of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells by chemopreventive agents with a resorcin-type structure. 1078 18

The modifying effects of dietary feeding of a polyisoprenylated benzophenone, garcinol, isolated from Garcinia indica fruit rind on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effects of garcinol on proliferating cell nuclear antigen (PCNA) index in ACF and activities of detoxifying enzymes of glutathione S-transferase (GST) and quinone reductase (QR) in liver. In addition, we examined the effects of garcinol on 12-O-tetradecanoylphorbol-13-acetate-induced O(2)(-) generation in differentiated human promyelocytic HL-60 cells and lipopolysaccharide (LPS)- and interferon (IFN)-gamma-induced nitric oxide (NO) generation in mouse macrophage RAW 264.7 cells. Western blotting analysis of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression was done in LPS- and IFN-gamma-treated mouse macrophage RAW 264.7 cells. Rats were given subcutaneous injections of AOM (15 mg/kg body wt) once a week for 3 weeks to induce ACF. They also received the experimental diet containing 0.01 or 0.05% garcinol for 5 weeks, starting 1 week before the first dosing of AOM. AOM exposure produced 97 +/- 15 ACF/rat at the end of the study (week 5). Dietary administration of garcinol caused significant reduction in the frequency of ACF: 72 +/- 15 (26% reduction, P < 0.01) at a dose of 0.01% and 58 +/- 8 (40% reduction, P < 0.001) at a dose of 0.05%. Garcinol administration significantly lowered PCNA index in ACF. Feeding of garcinol significantly elevated liver GST and QR activities. In addition, garcinol could suppress O(2)(-) and NO generation and expression of iNOS and COX-2 proteins. These findings might suggest possible chemopreventive ability of garcinol, through induction of liver GST and QR, inhibition of O(2)(-) and NO generation and/or suppression of iNOS and COX-2 expression, on colon tumorigenesis.
Carcinogenesis 2000 Jun
PMID:Prevention of colonic aberrant crypt foci by dietary feeding of garcinol in male F344 rats. 1083 8

Cyclooxygenase-2 (COX-2; Ptgs2) acts as a tumor promoter in rodent models for colorectal cancer, but its precise role in carcinogenesis remains unclear. We evaluated the contribution of host-derived COX-1 and COX-2 in tumor growth using both genetic and pharmacological approaches. Lewis lung carcinoma (LLC) cells grow rapidly as solid tumors when implanted in C57BL/6 mice. We found that tumor growth was markedly attenuated in COX-2(-/-), but not COX-1(-/-) or wild-type mice. Treatment of wild-type C57BL/6 mice bearing LLC tumors with a selective COX-2 inhibitor also reduced tumor growth. A decrease in vascular density was observed in tumors grown in COX-2(-/-) mice when compared with those in wild-type mice. Because COX-2 is expressed in stromal fibroblasts of human and rodent colorectal carcinomas, we evaluated COX-2(-/-) mouse fibroblasts and found a 94% reduction in their ability to produce the proangiogenic factor, VEGF. Additionally, treatment of wild-type mouse fibroblasts with a selective COX-2 inhibitor reduced VEGF production by 92%.
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PMID:Host cyclooxygenase-2 modulates carcinoma growth. 1084 6

There are about 600 million betel quid (BQ) chewers in the world. BQ chewing is associated with increased incidence of oral cancer and submucous fibrosis. In this study, areca nut (AN) extract (200-800 microg/ml) induced the prostaglandin E(2) (PGE(2)) production by 1. 4-3.4-fold and 6-keto-PGF(1 alpha) production by 1.1-1.7-fold of gingival keratinocytes (GK), respectively, following 24 h of exposure. Exposure of GK to AN extract (>400 microg/ml) led to cell retraction and intracellular vacuoles formation. At concentrations of 800 and 1200 microg/ml, AN extract induced cell death at 21-24 and 32-52% as detected by MTT assay and cellular lactate dehydrogenase release, respectively. Interestingly, AN-induced morphological changes of GK are reversible. GK can still proliferate following exposure to AN extract. Cytotoxicity of AN extract cannot be inhibited by indomethacin (1 microM) and aspirin (50 microM), indicating that prostaglandin (PG) production is not the major factor responsible for AN cytotoxicity. PGE(2) exhibited little effect on the growth of GK at concentrations ranging from 100-1000 pg/ml. Stimulating GK production of PGs by AN extract could be due to induction of cyclooxygenase-2 (COX-2) mRNA expression and protein production. These results suggest that AN ingredients are critical in the pathogenesis of oral submucous fibrosis and oral cancer via their stimulatory effects on the PGs, COX-2 production and associated tissue inflammatory responses. AN cytotoxicity to GK is not directly mediated by COX-2 stimulation and PG production.
Carcinogenesis 2000 Jul
PMID:Areca nut extract up-regulates prostaglandin production, cyclooxygenase-2 mRNA and protein expression of human oral keratinocytes. 1087 15

Overexpression of cyclooxygenase-2 (COX-2) is seen in a high percentage of human colon tumors, lung adenocarcinomas and other cancers. Inhibition of this enzyme represses human colon tumorigenesis and decreases lung tumor multiplicity in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-exposed A/J mice. The purpose of this investigation was to characterize the expression of cyclooxygenase-2 (COX-2) during tumor progression in the A/J mouse lung and to compare the results with expression in other cancer-susceptible and several cancer-resistant mouse strains. Analysis of normal A/J mouse lung showed that type II alveolar epithelial cells express high levels of COX-2 protein and mRNA, indicating that COX-2 is present constitutively in this tumor progenitor cell prior to any carcinogen exposure. Examination of lung-cancer-resistant (C3H/HeJ, C57BL/6J, DBA/2J) and other lung-cancer-susceptible (A/WySnJ, SWR/J) strains showed similar levels of COX-2 mRNA expression in the three susceptible strains and lower levels of expression in two of the resistant strains, indicating a possible correlation between COX-2 expression in type II cells and lung cancer susceptibility. COX-2 protein expression was observed in A/J lung tumors at all stages of development. Variation and occasional absence of protein expression were also observed in A/J lung tumors, particularly in adenomas and adenocarcinomas, suggesting that COX-2 is not obligatory for maintenance of the malignant phenotype. In support of this conclusion, treatment of xenografted cell lines derived from malignant murine pulmonary tumors with COX-2 inhibitors produced only a slight repression of growth. However, the frequent expression of COX-2 in early lesions in the A/J mouse lung combined with the known reduction in tumor number in animals treated with COX-2 inhibitors prior to carcinogen exposure indicate that COX-2 could be a promising target for lung cancer chemoprevention. In addition, high levels of COX-2 expression in the normal tumor-progenitor cells of lung-cancer-sensitive mice indicate that COX-2 may play a role in lung cancer susceptibility.
Carcinogenesis 2000 Jul
PMID:Cyclooxygenase-2 expression is abundant in alveolar type II cells in lung cancer-sensitive mouse strains and in premalignant lesions. 1087 16

Wnt family members are critical in developmental processes and have been shown to promote carcinogenesis when ectopically expressed in the mouse mammary gland. The gene expression pattern mediated by Wnt is pivotal for these diverse responses. The Wnt pathway has been conserved among different species. Genetic studies have shown that Wnt effects are mediated, at least in part, by beta-catenin, which regulates transcription of "downstream genes." Wnt stimulation inactivates glycogen-synthase kinase-3beta (GSK-3) with subsequent stabilization of beta-catenin, which after heterodimerizing with lymphocyte enhancer factor-1/T-cell factor cofactors stimulates transcription. To establish whether Wnt-stimulated transcription is mediated solely by beta-catenin, a comparison was made of gene expression profiles in response to Wnt-3, overexpression of beta-catenin, and inhibition of GSK-3. Infection of cells with Wnt-3 and inhibition of GSK-3 regulate a set of genes that include cyclooxygenase-2 and periostin. Interestingly, overexpression of beta-catenin or reducing beta-catenin levels with antisense oligonucleotide transfection did not have any effect on cyclooxygenase-2 or periostin expression, thereby defining a Wnt pathway, which cannot be mimicked by beta-catenin overexpression.
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PMID:Regulation of cyclooxygenase-2 and periostin by Wnt-3 in mouse mammary epithelial cells. 1088 77

Flavonoids are polyphenolic compounds that occur ubiquitously in plants. They are discussed to represent cancer preventive food components in a human diet that is rich in fruits and vegetables. To understand the molecular basis of the putative anticancer activity of flavonoids, we investigated whether and how the core structure of the flavones, 2-phenyl-4H-1-benzopyran-4-one (flavone) affects proliferation, differentiation, and apoptosis in HT-29 human colon cancer cells. Moreover, the effects of flavone in transformed epithelial cells were compared with those obtained in nontransformed primary mouse colonocytes. Proliferation, differentiation, and apoptosis in transformed as well as nontransformed colon cells were measured by fluorescence-based techniques. Apoptosis was also determined by changes in membrane permeability, FACScan analysis, and detection of DNA fragmentation. Semiquantitative reverse transcription PCR was performed to assess the effects of flavone on transcript levels. Flavone was found to reduce cell proliferation in HT-29 cells with an EC(50) value of 54.8 +/- 1.3 microM and to potently induce differentiation as well as apoptosis. The flavonoid proved to be a stronger apoptosis inducer than the clinically established antitumor agent camptothecin. The effects of flavone in HT-29 cells were associated with changed mRNA levels of cell-cycle- and apoptosis-related genes including cyclooxygenase-2 (COX-2), nuclear transcription factor kappaB (NF-kappaB), and bcl-X(L). Moreover, flavone, but not camptothecin, displayed a high selectivity for the induction of apoptosis and of growth inhibition only in the transformed colonocytes. In conclusion, the plant polyphenol flavone induces effectively programmed cell death, differentiation, and growth inhibition in transformed colonocytes by acting at the mRNA levels of genes involved in these processes. Because these genes play a crucial role in colon carcinogenesis, flavone may prove to be a potent new cytostatic compound with improved selectivity toward transformed cells.
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PMID:Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells. 1091 56

Cyclooxygenase-2 (COX-2) plays an important role in carcinogenesis. Investigation of the suppressive action of twelve flavonoids of different chemical classes on the transcriptional activity of the COX-2 gene in human colon cancer DLD-1 cells using a reporter gene assay have revealed quercetin to be the most potent suppressor of COX-2 transcription (IC50 = 10.5 microM), while catechin and epicatechin showed weak activity (IC50 = 415.3 microM). Flavonoids have three heterocyclic rings as a common structure. A structure-activity study indicated that the number of hydroxyl groups on the B ring and an oxo group at the 4-position of the C ring are important in the suppression of COX-2 transcriptional activity. A low electron density of the oxygen atom in the hydroxyl group of the A ring was also important. Further examination of the role of the hydroxyl group in the A ring showed that bromination of resacetophenone to give 3,5-dibromo-2,4-dihydroxyacetophenone resulted in a 6.8-fold increase in potency for suppressing COX-2 promoter activity. These results provide a basis for the design of improved suppressors of COX-2 transcriptional activity.
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PMID:Suppression by flavonoids of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells: structure-activity relationship. 1092 Feb 75


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