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)

MK-886, an inhibitor of the 5-lipoxygenase-activating protein (FLAP), potently suppresses leukotriene biosynthesis in intact cells and is frequently used to define a role of the 5-lipoxygenase (EC 1.13.11.34) pathway in cellular or animal models of inflammation, allergy, cancer, and cardiovascular disease. Here we show that MK-886 also interferes with the activities of cyclooxygenases (COX, EC 1.14.99.1). MK-886 inhibited isolated COX-1 (IC(50)=8 microM) and blocked the formation of the COX-1-derived products 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid (12-HHT) and thromboxane B(2) in washed human platelets in response to collagen as well as from exogenous arachidonic acid (IC(50)=13-15 microM). Isolated COX-2 was less affected (IC(50)=58 microM), and in A549 cells, MK-886 (33 microM) failed to suppress COX-2-dependent 6-keto-prostaglandin (PG)F(1alpha) formation. The distinct susceptibility of MK-886 towards COX-1 and -2 is apparent in automated molecular docking studies that indicate a preferred binding of MK-886 to COX-1 into the active site. MK-886 (10 microM) inhibited COX-1-mediated platelet aggregation induced by collagen or arachidonic acid whereas thrombin- or U-46619-induced (COX-independent) aggregation was not affected. Since leukotrienes and prostaglandins share (patho)physiological properties in the development and regulation of carcinogenesis, inflammation, and vascular functions, caution should be used when interpreting data where MK-886 is used as tool to determine the involvement of FLAP and/or the 5-lipoxygenase pathway in respective experimental models.
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PMID:MK-886, an inhibitor of the 5-lipoxygenase-activating protein, inhibits cyclooxygenase-1 activity and suppresses platelet aggregation. 1923 10

Arachidonic acid (AA) and its metabolites have recently generated a heightened interest due to growing evidence of their significant role in cancer biology. Thus, inhibitors of the AA cascade, first and foremost COX inhibitors, which have originally been of interest in the treatment of inflammatory conditions and certain types of cardiovascular disease, are now attracting attention as an arsenal against cancer. An increasing number of investigations support their role in cancer chemoprevention, although the precise molecular mechanisms that link levels of AA, and its metabolites, with cancer progression have still to be elucidated. This article provides an overview of the AA cascade and focuses on the roles of its inhibitors and their implication in cancer treatment. In particular, emphasis is placed on the inhibition of cell proliferation and neo-angiogenesis through inhibition of the enzymes COX-2, 5-LOX and CYP450. Downstream effects of inhibition of AA metabolites are analysed and the molecular mechanisms of action of a selected number of inhibitors of catalytic pathways reviewed. Lastly, the benefits of dietary omega-3 fatty acids and their mechanisms of action leading to reduced cancer risk and impeded cancer cell growth are mentioned. Finally, a proposal is put forward, suggesting a novel and integrated approach in viewing the molecular mechanisms and complex interactions responsible for the involvement of AA metabolites in carcinogenesis and the protective effects of omega-3 fatty acids in inflammation and tumour prevention.
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PMID:Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis. 1923 26

Lung cancer is the leading cause of cancer death in the United States and five-year survival remains low. Numerous studies have shown that chronic inflammation may lead to progression of carcinogenesis. As a result of inflammatory stimulation, arachidonic acid (AA) metabolism produces proliferation mediators through complex and dynamic interactions of the products of the LOX/COX enzymes. One important mediator in the activation of the AA pathways is the nuclear protein PPARgamma. Targeting LOX/COX enzymes and inducing activation of PPARgamma have resulted in significant reduction of cell growth in lung cancer cell lines. However, specific COX-inhibitors have been correlated with an increased cardiovascular risk. Clinical applications are still being explored with a novel generation of dual LOX/COX inhibitors. PPARgamma activation through synthetic ligands (TZDs) has revealed a great mechanistic complexity since effects are produced through PPARgamma-dependent and -independent mechanisms. Furthermore, PPARgamma could also be involved in regulation of COX-2. Overexpression of PPARgamma has reported to play a role in control of invasion and differentiation. Exploring the function of PPARgamma, in this new context, may provide a better mechanistic model of its role in cancer and give an opportunity to design a more efficient therapeutic approach in combination with LOX/COX inhibitors.
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PMID:Combination Therapy of PPARgamma Ligands and Inhibitors of Arachidonic Acid in Lung Cancer. 1927 4

It has been suggested that epithelial cyclooxygenase-2 (COX-2) promotes oral carcinogenesis and carcinoma malignancy through increased prostaglandin E(2) (PGE(2)) production. Although oral squamous cell carcinomas (OSCC) often express COX-2, they may also produce PGE(2) in a COX-1-dependent manner. We used 6 isolated cell lines to investigate which COX isoforms OSCC may use for PGE(2) production. COX-1 and -2 expression patterns divided the 6 OSCC cell lines into 3 distinct groups: both COX isoforms low, only COX-1 high, or both COX isoforms high. Multicolor immunohistofluorescence staining confirmed the COX-expression profiles in organotypic 3D cultures and the COX-2 dominance in OSCC tumors. Epidermal growth factor (EGF) stimulation induced COX-2 (but not COX-1) expression and increased PGE(2) production, which was attenuated by COX-2 (but not COX-1) specific inhibition or siRNA-mediated COX-2 gene knockdown. Thus, PGE(2) production in OSCC cell lines was COX-2-dependent.
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PMID:PGE2 production in oral cancer cell lines is COX-2-dependent. 1927 89

Cancer cells produce high amounts of reactive oxygen species (ROS) and evade apoptosis. Hydroperoxides support proliferation, invasion, migration and angiogenesis, but at higher levels induce apoptosis, thus being pro- and anti-carcinogenic. Accordingly, glutathione peroxidases (GPxs) regulating hydroperoxide levels might have dual roles too. GPx1, clearly an antioxidant enzyme, is down-regulated in many cancer cells. Its main role would be prevention of cancer initiation by ROS-mediated DNA damage. GPx2 is up-regulated in cancer cells. GPx1/GPx2 double knockout mice develop colitis and intestinal cancer. However, GPx2 knockdown cancer cells grow better in vitro and in vivo probably reflecting the physiological role of GPx2 in intestinal mucosa homeostasis. GPx2 counteracts COX-2 expression and PGE(2) production, which explains its potential to inhibit migration and invasion of cultured cancer cells. Overexpression of GPx3 inhibits tumor growth and metastasis. GPx4 is decreased in cancer tissues. GPx4-overexpressing cancer cells have low COX-2 activity and tumors derived therefrom are smaller than from control cells and do not metastasize. Collectively, GPxs prevent cancer initiation by removing hydroperoxides. GPx4 inhibits but GPx2 supports growth of established tumors. Metastasis, but also apoptosis, is inhibited by all GPxs. GPx-mediated regulation of COX/LOX activities may be relevant to early stages of inflammation-mediated carcinogenesis.
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PMID:Glutathione peroxidases in different stages of carcinogenesis. 1928 49

Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) play a role in inflammation and carcinogenesis. Biomarkers that reflect tobacco smoke-induced tissue injury are needed. In this study, levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E(4) (LTE(4)), biomarkers of the COX and 5-LO pathways, were compared in never smokers, former smokers, and current smokers. The effects of celecoxib, a selective COX-2 inhibitor, on levels of PGE-M and LTE(4) were determined. Baseline levels of PGE-M and LTE(4) were positively associated with smoking status; levels of PGE-M and LTE(4) were higher in current versus never smokers. Treatment with 200 mg celecoxib twice daily for 6 +/- 1 days led to a reduction in urinary PGE-M levels in all groups but exhibited the greatest effect among subjects with high baseline PGE-M levels. Thus, high baseline PGE-M levels in smokers reflected increased COX-2 activity. In individuals with high baseline PGE-M levels, treatment with celecoxib led to a significant increase in levels of urinary LTE(4), an effect that was not found in individuals with low baseline PGE-M levels. In conclusion, increased levels of urinary PGE-M and LTE(4) were found in human smokers, a result that may reflect subclinical lung inflammation. In individuals with high baseline levels of PGE-M (elevated COX-2 activity), celecoxib administration shunted arachidonic acid into the proinflammatory 5-LO pathway. Because 5-LO activity and LTE(4) have been suggested to play a role in cardiovascular disease, these results may help to explain the link between use of COX-2 inhibitors and cardiovascular complications.
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PMID:Levels of prostaglandin E metabolite and leukotriene E(4) are increased in the urine of smokers: evidence that celecoxib shunts arachidonic acid into the 5-lipoxygenase pathway. 1933 21

Possible altered gene expression patterns in bladder tumour carcinogenesis in rat bladder cancers induced by BBN [N-butyl-N-(4-hydroxybutyl)nitrosamine] was examined by cDNA microarray analysis of gene expression profiles. Thirty Sprague-Dawley rats were given drinking water containing 0.05% BBN ad libitum for 24 to 28 weeks. Equal numbers of control rats were given tap water without BBN. After treatment, the rat bladders were excised for RNA extraction and histopathological examinations. Total RNAs were extracted from rat transitional cell carcinoma (TCC) tissues and micro-dissected normal rat bladder epithelia. The atlas glass rat microarray was used, which included oligonucleotides of 1081 rat genes. Some of the up-regulated genes in rat bladder TCCs were further confirmed by Northern blotting. Our results showed that the transcriptions of 30 genes were significantly elevated in the rat bladder TCCs, and these included fly proto-oncogene, Lipocortin 2, COX IV, COX V a, and cathepsin D. Also, 15 genes were significantly down-regulated in the rat bladder TCCs and they included B7.1, TNFr1, APOA1 and VHL. The results of cDNA microarray analysis demonstrated that normal rat bladder epithelia and bladder TCC exhibited different and specific gene statement profiles. The increased expressions of the identified genes may play an important role in the chemically induced bladder carcinogenesis.
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PMID:Identification of differently expressed genes in chemical carcinogen-induced rat bladder cancers. 1939 9

mPGES-1 (microsomal prostaglandin E synthase-1) is a stimulus-inducible enzyme that functions downstream of COX (cyclo-oxygenase)-2 in the PGE2 (prostaglandin E2)-biosynthesis pathway. Although COX-2-derived PGE2 is known to play a role in the development of various tumours, the involvement of mPGES-1 in carcinogenesis has not yet been fully understood. In the present study, we used LLC (Lewis lung carcinoma) cells with mPGES-1 knockdown or overexpression, as well as mPGES-1-deficient mice to examine the roles of cancer cell- and host-associated mPGES-1 in the processes of tumorigenesis in vitro and in vivo. We found that siRNA (small interfering RNA) silencing of mPGES-1 in LLC cells decreased PGE2 synthesis markedly, accompanied by reduced cell proliferation, attenuated Matrigel invasiveness and increased extracellular matrix adhesion. Conversely, mPGES-1-overexpressing LLC cells showed increased proliferating and invasive capacities. When implanted subcutaneously into wild-type mice, mPGES-1-silenced cells formed smaller xenograft tumours than did control cells. Furthermore, LLC tumours grafted subcutaneously into mPGES-1-knockout mice grew more slowly than did those grafted into littermate wild-type mice, with concomitant decreases in the density of microvascular networks, the expression of pro-angiogenic vascular endothelial growth factor, and the activity of matrix metalloproteinase-2. Lung metastasis of intravenously injected LLC cells was also significantly less obvious in mPGES-1-null mice than in wild-type mice. Thus our present approaches provide unequivocal evidence for critical roles of the mPGES-1-dependent PGE2 biosynthetic pathway in both cancer cells and host microenvironments in tumour growth and metastasis.
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PMID:Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis. 1984 4

COX-2 (cyclo-oxygenase 2), an inducible form of the enzyme that catalyses the first step in the synthesis of prostanoids, is associated with inflammatory diseases and carcinogenesis, which is suspected to promote angiogenesis and tissue invasion of tumours and resistance to apoptosis. COX-2 is also involved in drug resistance and poor prognosis of many neoplastic diseases or cancers. The activation of the COX-2/PGE2 (prostaglandin E2)/prostaglandin E receptor signal pathway can up-regulate the expression of all three ABC (ATP-binding-cassette) transporters, MDR1/P-gp (multidrug resistance/P-glycoprotein), MRP1 (multidrug-resistance protein 1) and BCRP (breast-cancer-resistance protein), which encode efflux pumps, playing important roles in the development of multidrug resistance. In addition, COX inhibitors inhibit the expression of MDR1/P-gp, MRP1 and BCRP and enhance the cytotoxicity of anticancer drugs. Therefore we can use the COX inhibitors to potentialize the effects of chemotherapeutic agents and reverse multidrug resistance to facilitate the patient who may benefit from addition of COX inhibitors to standard cytotoxic therapy.
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PMID:Cyclo-oxygenase 2 up-regulates the effect of multidrug resistance. 2000 74

Oral squamous cell carcinomas induced in rats by 4-nitroquinoline-1-oxide (NQO) show substantial overexpression of cyclooxygenase-2 (COX-2) when compared with adjacent phenotypically normal oral tissues. By contrast, neither 5-lipoxygenase (LOX) nor 12-LOX is overexpressed in rat oral cancers. Two chemoprevention studies were done to test the resulting hypothesis that COX-2 is a useful target for oral cancer chemoprevention in the rat. In both studies, male F344 rats received drinking water exposure to NQO (20 ppm) for 10 weeks, followed by administration of chemopreventive agents from week 10 until study termination at week 26. In the first study, groups of rats were fed basal diet (control), or basal diet supplemented with the selective COX-2 inhibitor celecoxib (500 or 1,500 mg/kg diet), the nonselective COX inhibitor piroxicam (50 or 150 mg/kg diet), or the 5-LOX inhibitor zileuton (2,000 mg/kg diet). In the second study, rats were fed basal diet (control) or basal diet supplemented with nitric oxide-naproxen (180 or 90 mg/kg diet), a nonselective COX inhibitor that shows reduced gastrointestinal toxicity. When compared with dietary controls, celecoxib decreased oral cancer incidence, cancer invasion score, and cancer-related mortality. Piroxicam decreased cancer-related mortality and cancer invasion score, whereas nitric oxide-naproxen decreased oral cancer incidence and cancer invasion score. By contrast, zileuton showed no chemopreventive activity by any parameter assessed. These data show that both selective and nonselective inhibitors of COX-2 can prevent NQO-induced oral carcinogenesis in rats. The chemopreventive activity of COX inhibitors may be linked to overexpression of their enzymatic target in incipient oral neoplasms.
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PMID:Overexpression of cyclooxygenase-2 in rat oral cancers and prevention of oral carcinogenesis in rats by selective and nonselective COX inhibitors. 2005 74


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