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)

Recent discoveries shed light on the importance of prostaglandin (PG) production in the development of skin cancer. Work by Fischer et al. demonstrates that skin tumor promotion caused by ultraviolet B radiation can be decreased by up to 89% by blocking cyclooxygenase-2 (COX-2) with the drug Celecoxib. A similar study showed that Celecoxib can decrease new tumor formation by 44% in mice that already have tumors. These studies demonstrate the importance of COX-2 and PGs in the development of squamous cell carcinoma. We have explored growth signaling in a model of skin tumor progression. Because changes in PG production have been implicated in skin carcinogenesis, we examined this pathway. We found that malignant cell lines secrete more prostaglandin E(2) (PGE(2)) than the parental cells. We observed increased expression of COX-1 and -2. We also found that these cells express the PGE(2) receptors EP1 and EP4. When the cells are grown in the presence of indomethacin, the growth rate of the malignant cells is decreased. This effect can be reversed by addition of PGE(2) or an EP1 agonist to the medium. Thus, we have shown that skin tumor cells depend in part on PGE(2) signaling through the EP1 prostanoid receptor for their in vitro growth.
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PMID:The growth of malignant keratinocytes depends on signaling through the PGE(2) receptor EP1. 1168 51

It is suggested that nonsteroidal antiinflammatory inhibitors alter the biology of colorectal carcinogenesis. Cyclooxygenase-2, one of target molecules of these drugs, is reported to be upregulated in cancer tissues. Cultured cells which were derived from intestinal epithelium and programmed to express COX-2 showed several phenotypic changes in favor of carcinogenesis, including resistance to apoptosis and enhancement of cell proliferation, angiogenesis, and invasion. Tumor growth implanted in COX-2 null mice was significantly attenuated, but not in COX-1 null or wild type mice, suggesting that COX-2 in stroma also has an important role in tumor growth. Moreover, PGE2, one of COX-2 metabolites, reversed these antitumor effects, indicating that inhibition of PGE2 production has a pivotal role in tumor suppression. However, NSAIDs show antitumor effects in cancer cells lacking COX-1 or COX-2 expression, and some derivatives lacking the ability to suppress COX activity show antitumor effects. These results suggest that COX independent pathway might be involved in antitumor effects of NSAIDs. For the development of novel and effective therapies, it is required to elucidate mechanisms underlying antitumor effects of NSAIDs.
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PMID:[COX-2 inhibitor and colon cancer]. 1172 71

The epidemiologic evidence and rodent studies suggest strongly that nonselective inhibitors of cyclooxygenase (COX) enzymes such as aspirin, inhibiting both COX-1 and COX-2 isoforms, reduce the incidence of and mortality from intestinal tumors. Genetically manipulated animals show that both Cox-1 and Cox-2 disruptions decrease the tumor yield, both in genetically predisposed and in carcinogen-treated mice. The mechanisms by which COX-1 and COX-2 deficiency decrease tumorigenesis are still unknown. Cox-2 overexpression increased the tumor yield in mammary glands of the multiparous, but not virginal female transgenic mice using the murine mammary tumor virus promoter. The Cox-2 protein was strongly induced during pregnancy and lactation. These data suggest that Cox-2 overexpression may be an important target for cancer chemoprevention. This finding was supported by the observed cancer-preventive effects of the COX-2-specific inhibitors in humans and in rodents. However, based on the available data, we cannot totally attribute the cancer preventive effects of nonsteroidal antiinflammatory drugs (NSAIDs) to COX-2 alone-even COX-1 may have an important role in cancer prevention as suggested by the Cox-1-deficient Min mice. It is likely that COX-1 plays a more important role in NSAID-induced toxicity in humans, such as in gastric ulcer formation-but inhibition of COX-2 may not be without toxic manifestations either, as suggested by the poor survival of the Cox-2-nulled mice. Combinations of COX-2 inhibitors with other agents that target other pathways in carcinogenesis may be a more efficacious and a less toxic strategy in cancer chemoprevention.
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PMID:Is COX-2 inhibition a panacea for cancer prevention? 1174 53

Cyclooxygenase (COX) is a key enzyme in arachidonic acid metabolism. Two isoforms of this enzyme have been identified: constitutive COX-1 and inducible COX-2. Recently, expression of COX-2 has been found in several human carcinomas. COX-2 expression may contribute to the synthesis of prostanoids, which relate to carcinogenesis and tumor progression. We investigated the expression of COX-2 in 175 human esophageal squamous cell carcinoma tissues using immunohistochemistry and evaluated the relationship with clinicopathological findings. In addition, due to the known relevance of p53 to carcinogenesis, we evaluated the expression of COX-2 and p53. Interestingly, cancer tissues with high COX-2 expression were found significantly more often in the middle and lower esophagus than in the cervical and upper esophagus (p = 0.0014). No significant differences were observed in other clinicopathological data such as age, sex, histopathological grading, lymphatic invasion, venous invasion, TNM clinical classification and patient prognosis. p53 expression was associated with the expression of COX-2 (p = 0.0122). Our findings suggest that COX-2 may play a role in the development of squamous cell carcinoma in the lower part of the thoracic esophagus.
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PMID:Expression of cyclooxygenase-2 is associated with carcinogenesis of the lower part of thoracic esophageal squamous cell carcinoma and p53 expression. 1181 43

Zerumbone (ZER), a sesquiterpene from the edible plant Zingiber zerumbet Smith, has recently been found to suppress tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein-Barr virus activation in a potent manner. In the present study, we evaluated the anti-inflammatory and chemopreventive potentials of ZER in a variety of cell culture experiments. ZER effectively suppressed TPA-induced superoxide anion generation from both NADPH oxidase in dimethylsulfoxide-differentiated HL-60 human acute promyelocytic leukemia cells and xanthine oxidase in AS52 Chinese hamster ovary cells. The combined lipopolysaccharide- and interferon-gamma-stimulated protein expressions of inducible nitric oxide synthase and cyclooxygenase (COX)-2, together with the release of tumor necrosis factor-alpha, in RAW 264.7 mouse macrophages were also markedly diminished. These suppressive events were accompanied with a combined decrease in the medium concentrations of nitrite and prostaglandin E(2), while the expression level of COX-1 was unchanged. ZER inhibited the proliferation of human colonic adenocarcinoma cell lines (LS174T, LS180, COLO205, and COLO320DM) in a dose-dependent manner, while the growth of normal human dermal (2F0-C25) and colon (CCD-18 Co) fibroblasts was less affected. It also induced apoptosis in COLO205 cells, as detected by dysfunction of the mitochondria transmembrane, Annexin V-detected translocation of phosphatidylserine, and chromatin condensation. Intriguingly, alpha-humulene, a structural analog lacking only the carbonyl group in ZER, was virtually inactive in all experiments conducted, indicating that the alpha,beta-unsaturated carbonyl group in ZER may play some pivotal roles in interactions with unidentified target molecule(s). Taken together, our results indicate that ZER is a food phytochemical that has distinct potentials for use in anti-inflammation, chemoprevention, and chemotherapy strategies.
Carcinogenesis 2002 May
PMID:Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: the alpha,beta-unsaturated carbonyl group is a prerequisite. 1241 47

Nonsteroidal anti-inflammatory drugs are widely reported to inhibit carcinogenesis in humans and in rodents. These drugs are believed to act by inhibiting one or both of the known isoforms of cyclooxygenase (COX). However, COX-2, and not COX-1, is the isoform most frequently reported to have a key role in tumor development. Here we report that homozygous deficiency of either COX-1 or COX-2 reduces skin tumorigenesis by 75% in a multistage mouse skin model. Reduced tumorigenesis was observed even though the levels of stable 7,12-dimethylbenz(a)anthracene-DNA adducts were increased about 2-fold in the COX-deficient mice compared with wild-type mice. The premature onset of keratinocyte terminal differentiation appeared to be the cellular event leading to the reduced tumorigenesis because keratin 1 and keratin 10, two keratins that indicate the commitment of keratinocytes to differentiate, were expressed 8-13-fold and 10-20-fold more frequently in epidermal basal cells of the COX-1-deficient and COX-2-deficient mice, respectively, than in wild-type mice. Papillomas on the COX-deficient mice also displayed the premature onset of keratinocyte terminal differentiation. However, loricrin, a late marker of epidermal differentiation, was not significantly altered, suggesting that it was the early stages of keratinocyte differentiation that were primarily affected by COX deficiency. Because keratin 5, a keratin associated with basal cells, was detected differently in papillomas of COX-1-deficient as compared with COX-2-deficient mice, it appears that the isoforms do not have identical roles in papilloma development. Interestingly, apoptosis, a cellular process associated with nonsteroidal anti-inflammatory drug-induced inhibition of tumorigenesis, was not significantly altered in the epidermis or in papillomas of the COX-deficient mice. Thus, both COX-1 and COX-2 have roles in keratinocyte differentiation, and we propose that the absence of either isoform causes premature terminal differentiation of initiated keratinocytes and reduced tumor formation.
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PMID:Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis. 1206 81

Cancer chemopreventive agents are designed to reduce the incidence of tumorigenesis by intervening at one or more stages of carcinogenesis. Recently, resveratrol, a natural product found in the diet of humans, has been shown to function as a cancer chemopreventive agent. Resveratrol was first shown to act as an antioxidant and antimutagenic agent, thus acting as an anti-initiation agent. Further evidence indicated that resveratrol selectively suppresses the transcriptional activation of cytochrome P-450 1A1 and inhibits the formation of carcinogen-induced preneoplastic lesions in a mouse mammary organ culture model. Resveratrol also inhibits the formation of 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted mouse skin tumors in the two-stage model. The enzymatic activities of COX-1 and -2 are inhibited by resveratrol in cell-free models, and COX-2 mRNA and TPA-induced activation of protein kinase C and AP-1-mediated gene expression are suppressed by resveratrol in mammary epithelial cells. In addition, resveratrol strongly inhibits nitric oxide generation and inducible nitric oxide synthase protein expression. NF kappa B is strongly linked to inflammatory and immune responses and is associated with oncogenesis in certain models of cancer, and resveratrol suppresses the induction of this transcription factor by a number of agents. The mechanism may involve decreasing the phosphorylation and degradation of I kappa B alpha. At the cellular level, resveratrol also induces apoptosis, cell cycle delay or a block in the G(1) --> S transition phase in a number of cell lines. Thus, resveratrol holds great promise for future development as a chemopreventive agent that may be useful for several disorders. Preclinical toxicity studies are underway that should be followed by human clinical trials.
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PMID:Cancer chemopreventive activity of resveratrol. 1207 74

Interest in chemoprevention in oncology using suppressants of prostaglandin (PG) synthesis has been stimulated by epidemiological observations that the use of aspirin and other non-steroidal inflammatory drugs (NSAIDs) is associated with reduced incidence of some cancers, including cancer of the breast. The main target of NSAID activity is the cyclooxygenase (COX) enzyme. Two isoforms of COX have been identified: COX-1, the constitutive isoform; and COX-2. the inducible form of the enzyme. COX-2 can undergo rapid induction in response to many factors such as bacterial lipopolysaccharides, growth factors, cytokines and phorbol esters. COX-2 is overexpressed in some malignancies including carcinoma of the breast. It has been suggested that such enhanced expression may lead to increased angiogenesis such that the inhibition of COX-2 might have a general anticancer effect via decreased blood vessel formation. In addition, an association between COX-2, its main product PGE2 and aromatase activity in human breast cancer suggests that such inhibitors might have an additional, specific prophylactic mechanism for this tumour. New COX-2 inhibitors are already licensed for use in the treatment of arthritis and are well tolerated. Their potential role in chemoprevention of mammary carcinogenesis in rats has already been investigated. What remains to be seen is if these findings can be extrapolated to human studies.
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PMID:Cyclooxygenase-2 (COX-2), aromatase and breast cancer: a possible role for COX-2 inhibitors in breast cancer chemoprevention. 1207 34

Our studies have focused on the role of arachidonic acid and its products in chemically and UV light-induced murine models of skin carcinogenesis, with an emphasis on determining the importance of prostaglandins (PGs), which are synthesized by the two isoforms of cyclooxygenase (COX). Different types of tumor promoters elevate COX-2 expression in keratinocytes, with little change in COX-1, suggesting that there are multiple signaling pathways by which COX-2 expression can be regulated. We found that the expression of both COX isoforms is increased by treatment with PGs and that this autoregulation occurs via PG receptors linked to a cAMP signaling pathway. We also observed that COX-2 is constitutively upregulated in papillomas and carcinomas from either chemical initiation-promotion or UV-irradiation carcinogenesis experiments. We next investigated cis- and transacting factors required for COX-2 expression. Two regions of the COX-2 promoter, an E box and a nuclear factor-IL6 (NF-IL6) site, were identified as positive regulatory elements through transient transfection with luciferase reporter vectors containing various 5'-flanking regions of the promoter. We found that overexpression of COX-2 in tumors maybe caused by a dysregulation in the expression pattern of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors. To demonstrate the importance of PG synthesis in the carcinogenesis process, several nonsteroidal anti-inflammatory (NSAIDs) drugs were administered either orally or topically during UV carcinogenesis. Dietary administration of indomethacin, piroxicam, or the selective COX-2 inhibitor celecoxib prevented the development of UV-induced skin cancers by up to 85%. In addition, celecoxib had therapeutic efficacy in that it caused regression of preexisting tumors. Topical administration of indomethacin after each UV exposure was also effective, suggesting that a postexposure approach to skin cancer prevention maybe effective. Collectively, these studies suggest that prostaglandins play a critical role in skin cancer development.
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PMID:Is cyclooxygenase-2 important in skin carcinogenesis? 1208 5

Inflammatory stimuli result in the production of cutaneous eicosanoids, which are known to contribute to the process of tumor promotion. Cyclooxygenase (COX), the rate-limiting enzyme for the production of prostaglandins (PG) from arachidonic acid, exists in at least two isoforms, COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and plays various physiological roles, whereas increased COX-2 expression is known to occur in several types of epithelial neoplasms. Enhanced PG synthesis is a potential contributing factor in UVB-induced nonmelanoma skin cancers (NMSC). Increased COX-2 staining occurs in murine skin neoplasms after chronic exposure to carcinogenic doses of UVB. In this study, immunohistochemical and Western blot analyses were employed to assess longitudinally COX-2 expression in a standard mouse UVB complete carcinogenesis protocol and in human basal cell carcinomas (BCC) and squamous cell carcinomas (SCC). During UVB irradiation of mice, COX-2 expression consistently increased in the hyperplastic skin, the benign papillomas and the SCC. COX-2 expression was also increased in human actinic keratoses, SCC and BCC as well as in murine SCC and BCC. The pattern of COX-2 expression was quite variable, occurring in a patchy distribution in some lesions with staining confined mainly to suprabasal cell layers. In general, COX-2 expression progressively became more extensive in benign papillomas and well-differentiated murine SCC. The staining was predominantly cytoplasmic and perinuclear in some focal areas in tissue stroma around both murine and human tumors. Western blot analysis confirmed negative COX-2 expression in normal skin, whereas acute UVB exposure resulted in increased enzyme expression, which continued to increase in developing papillomas and SCC. Because of the evidence indicating a pathogenic role for eicosanoids in murine and human skin neoplasms, we performed studies to assess the anti-inflammatory and anticarcinogenic effects of green tea extracts, which are potent antioxidants. Acute exposure of the human skin to UVB (minimum erythema dose x 4) caused a transient enhancement of the COX-2 expression, which reverted to baseline within hours; however, in murine skin the expression persisted for several days. Pretreatment with the topically applied green tea extract (1 mg/cm2) largely abrogated the acute COX-2 response to UVB in mice or humans. In summary, enhanced COX-2 expression serves as a marker of epidermal UVB exposure for murine and human NMSC. These results suggest that COX-2 inhibitors could have potent anticarcinogenic effects in UVB-induced skin cancer.
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PMID:Cyclooxygenase-2 expression in murine and human nonmelanoma skin cancers: implications for therapeutic approaches. 1212 10


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