Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The increased expression of cyclooxygenase (COX)-2 significantly enhances carcinogenesis and inflammatory reactions, and its regulation may be a reasonable target for cancer chemoprevention. We demonstrated previously that deguelin inhibits proliferation of premalignant human bronchial epithelial (HBE) cells, such as 1799 cells and squamous HBE cells, by regulating phosphatidylinositol-3-kinase Akt activity, which is involved in COX-2 expression. We sought to determine the effect of deguelin on COX-2 expression in squamous HBE cells. Deguelin strongly inhibited COX-2 expression in squamous HBE cells, without affecting the COX-1 protein level. Deguelin inhibited proliferation of a variety of non-small cell lung carcinoma (NSCLC) cell lines through apoptosis and induced Bax expression in the H322 NSCLC and squamous HBE cells. Deguelin treatment did not affect Bcl-2 protein levels but increased expression levels of the proapoptotic protein p53 and the cyclin-dependent kinase inhibitors p21 and p27 in the squamous HBE cells. The sensitivity of the squamous HBE and NSCLC cells to deguelin and the inhibitory effects of deguelin on COX-2 expression in the squamous HBE cells indicate that regulation of COX-2 expression is involved in the chemopreventive action of deguelin in lung cancer.
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PMID:Deguelin-induced inhibition of cyclooxygenase-2 expression in human bronchial epithelial cells. 1487 87

Malignant mesothelioma (MM) remains the most lethal pleural, peritoneal and pericardial cancer. Here, we characterize the effects of nonsteroidal anti-inflammatory agents (NSAIDs) on in vitro and in vivo experimental MM models. Unlike primary normal mesothelial cells, the selective cyclooxygenase (COX)-2 inhibitor celecoxib reduced the in vitro proliferation of several MM cells derived from previously untreated MM patients. Moreover, celecoxib significantly inhibited MM cell colony formation in soft agarose (63-78% at 5 x 10(-5) M; p < or = 0.05) and it elicited remarkable antitumor activity, leading to long-term survival in >37% of nude mice bearing intraperitoneal MM. Celecoxib was more efficient in inhibiting MM cell growth than acetylsalicylic acid (10(-6) M-10(-2) M), indometacin (10(-6) M-10(-2) M) and the COX-2 inhibitor NS-398 (10(-6) M-10(-4) M). Efficacy of these different compounds was not related to the amount of COX-2 protein levels present on MM cells. Celecoxib, in a dose- and time-dependent manner, induced MM cell apoptosis, which involved decreased Akt phosphorylation, loss of Bcl-2 and Survivin protein expression and caspase-3 activation. Furthermore, vascular endothelial growth factor (VEGF), an MM autocrine growth factor and Akt inducer, rescued celecoxib-induced apoptosis and Akt dephosphorylation. When the VEGF receptor (KDR/Flk-1) inhibitor, SU-1498, was used in combination with celecoxib, IC50 of celecoxib in vitro was reduced up to 65%. These data demonstrate that celecoxib may have antitumor properties in MM and provide a rationale for the therapeutic use of celecoxib in combination with a selective VEGF inhibitor.
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PMID:Preclinical evaluation of the nonsteroidal anti-inflammatory agent celecoxib on malignant mesothelioma chemoprevention. 1496 68

The expression of cyclooxygenase (COX)-2 is increased in human cancers including cholangiocarcinoma. This study was designed to evaluate the effect and mechanisms of the selective COX-2 inhibitor celecoxib in the growth control of human cholangiocarcinoma cells. Immunohistochemical analysis using human cholangiocarcinoma tissues showed increased levels of COX-2 as well as phospho-Akt (Thr (308)), a protein kinase activated by COX-2-mediated prostaglandins, in human cholangiocarcinoma cells. Treatment of cultured human cholangiocarcinoma cells (HuCCT1, SG231, and CCLP1) with celecoxib resulted in a dose- and time-dependent reduction of cell viability. Fluorescence microscopy, Western blot, and caspase activity assays demonstrated that celecoxib induced morphological features of apoptosis, activation of caspase-9 and caspase-3, and release of cytochrome c. The celecoxib-induced cell death was significantly blocked by N-benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone, a wide-spectrum caspase inhibitor. Furthermore, cholangiocarcinoma cells treated with celecoxib showed significant reduction of Akt phosphorylation, whereas the levels of Bcl-2 and Bax were not altered. Inhibition of Akt activation by LY294002 significantly decreased the viability of human cholangiocarcinoma cells. These findings suggest that celecoxib inhibits cholangiocarcinoma growth partly through induction of apoptosis and inhibition of Akt phosphorylation.
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PMID:The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells. 1502 50

Experimental and epidemiologic studies have demonstrated that nonsteroidal antiinflammatory drugs (NSAIDs) are effective in the prevention of human cancers. Nonsteroidal antiinflammatory drugs inhibit the cyclooxygenase (COX) enzyme that functions to convert arachidonic acid to prostaglandins (PGs). Cyclooxygenase-2, a key COX isoenzyme, is rapidly induced in response to inflammatory stimuli, growth factors, cytokines, and promoters of neoplastic growth. Cyclooxygenase-2-catalyzed reactions may be involved in carcinogenesis via 2 distinct mechanisms: (1). DNA damage and (2). PG-mediated effects. Reactions mediated by COX-2 form reactive oxygen species that can directly induce the oxidation of DNA or instigate the bioactivation of carcinogens. Prostaglandin E2, a byproduct of COX-2-mediated arachidonic acid metabolism, exhibits several biologic actions that have been shown to promote tumorigenesis and tumor progression. These actions include increased cell proliferation, promotion of angiogenesis, and the elevated expression of the antiapoptotic protein Bcl-2. In addition, PGE2 decreases natural killer cell activity and alters immune surveillance. In vitro experimental studies find that COX-2 inhibitors decrease cellular proliferation, increase apoptosis, and modulate genes involved in cell cycle regulation. Evidence from animal studies supports a role for NSAIDs in prostate cancer (CaP) prevention. Population-based studies have observed a reduced incidence of CaP among men using NSAIDs. Because CaP evolves slowly and rarely strikes men before the sixth or seventh decade of life, any strategy to delay or lengthen the time to development of clinically evident CaP, such as chemoprevention strategies, would greatly impact the natural history of this disease. Recent progress and critical analyses in the roles of COX-2 inhibition on prostate carcinogenesis and CaP prevention will be presented.
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PMID:The role of cyclooxygenase-2 inhibition for the prevention and treatment of prostate carcinoma. 1504 Aug 74

The present report is of immunohistochemical and cell biological studies on cyclooxygenase(COX)-2, Bcl-2 and Ki-67 in pleomorphic adenoma (n = 35). Pleomorphic adenomas from oral minor glands (n = 15), parotid gland (n = 11), Submandibular gland (n = 8) were studied and sublingual gland (n = 1). Expression of COX-2, Bcl-2 and Ki-67 was examined immunohistologically. Immunostaining intensity of COX-2 and Bcl-2 was classified into expression levels from +3 to 0. The positivity to Ki-67 was evaluated by counting the number of positive cells per 1000 cells, and the values were expressed in as percentage. Apoptotic cells were detected using the modified TUNEL method. Expression of COX-2 mRNA was analyzed by real time PCR using fresh tissues of 4 cases. The relationship between morphological findings and the level of COX-2 mRNA expression was analyzed using a laser capture microdissection (LCM). The results of immunohistochemistry and gene analysis using LCM revealed expression of COX-2 mainly in luminar tumor cells. Expression of COX-2 in pleomorphic adenoma was correlated with expression of Bcl-2 statistically (p = 0.044 < 0.05, r = 0.342). There was only a small number of apoptotic cells cells, and intensity of expression of TUNEL was not correlated with the expression of COX-2 (p = 0.463 > 0.05, r = -0.128). There was no statistical correlation between COX-2 and Ki-67 (p = 0.97 > 0.05, r = -0.07). It is suggested that COX-2 may inhibit apoptosis mediating Bcl-2 expression in pleomorphic adenoma, rather than playing a role in cell proliferation.
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PMID:Expression of cyclooxygenase-2, Bcl-2 and Ki-67 in pleomorphic adenoma with special reference to tumor proliferation and apoptosis. 1538 Jan 75

While enhanced expression of cyclooxygenase (COX)-2 has been observed in human skin epidermal cancer, the mechanisms underlying COX-2 expression have not been completely elucidated. Recently, a role for the phosphatidylinositol-3 (PI3) kinase pathway in COX-2 expression has attracted attention. We investigated COX-2 expression, PI3 kinase activity, and the phosphorylation level of Akt, a downstream effector of PI3 kinase, in the human skin cancer cell line HSC-5. Compared to the nontumorigenic keratinocyte HaCaT, in HSC-5 cells, COX-2 protein expression and PI3 kinase activity were increased. The PI3 kinase inhibitor LY294002 reduced COX-2 expression in HSC-5 cells and, contrary to our expectation, the phosphorylation of Akt was significantly decreased. The expression of Bcl-2, which is regulated by Akt, was reduced, and apoptosis was induced in HSC-5 cells compared to HaCaT cells. COX-2 inhibitor NS398 up-regulated Akt phosphorylation. These results imply that constitutively over-expressed COX-2 down-regulates the Akt phosphorylation through a negative feedback mechanism.
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PMID:Negative feedback regulation of phosphatidylinositol 3-kinase/Akt pathway by over-expressed cyclooxygenase-2 in human epidermal cancer cells. 1549 14

Celecoxib is a potent nonsteroid antiinflammatory drug (NSAID) that has shown great promise in cancer chemoprevention and treatment. The tumor suppression activity of celecoxib and other NSAIDs have been related to the induction of apoptosis in many cancer cell lines and animal models. While celecoxib is a specific inhibitor of cyclooxygenase (COX)-2, recent data indicate that its apoptotic properties may also be mediated through COX-independent pathways. In our study, we evaluated second generation celecoxib derivatives, lacking COX-2 inhibitory activity, in a premalignant and malignant human oral cell culture model to determine their potential anticancer effect and mechanisms responsible for the COX-independent apoptotic activity. Celecoxib and its derivatives delayed the progression of cells through the G(2)/M phase and induced apoptosis. The derivatives with apolar substituents at the terminal phenyl moiety of celecoxib greatly enhanced apoptosis and cell cycle delay. Apoptosis and cell cycle arrest appeared to be independent of derivative induced inhibition of PDK1 and phosphorylation of Akt and Erk1/2. Derivatives induced apoptosis was mediated by the cleavage and activation of caspase-9 and caspase-3, but not caspase 8, implicating the mitochondrial pathway for apoptosis induction. Inhibitors of caspase-3 and caspase-9 and cyclosporin A, a mitochondrial membrane potential stabilizer, attenuated derivative induced apoptosis. Inhibition of caspase-3 prevented the activation of caspase 8, while the inhibition of caspase-9 inhibitor blocked activation of both caspase 3 and 8 by the derivatives. Apoptosis was independent of Bcl-2. These results indicate that the second generation celecoxib derivatives induce apoptosis in human oral cancer lines by the disruption of mitochondrial membrane potential activating caspase 9 and downstream caspase 3 and 8. This suggests that the modification of the celecoxib structure can lead to highly effective COX-independent growth inhibitory and apoptotic agents in chemoprevention and therapy.
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PMID:Celecoxib derivatives induce apoptosis via the disruption of mitochondrial membrane potential and activation of caspase 9. 1549 25

Expression and pharmacological studies support a contribution of cyclooxygenase (COX)-2 to mammary gland tumorigenesis. In a recent transgenic study, mouse mammary tumor virus promoter-driven COX-2 expression in mouse mammary glands was shown to result in alveolar hyperplasia, dysplasia, and carcinomas after multiple rounds of pregnancy and lactation. In the study presented here, the effects of constitutive COX-2 overexpression in keratin 5-positive myoepithelial and luminal cells, driven by the keratin 5 promoter in a hormone-independent manner, was investigated. In nulliparous female mice, aberrant COX-2 overexpression correlated with increased prostaglandin (PG) E(2) levels and caused cystic duct dilatations, adenosis, and fibrosis whereas carcinomas developed rarely. This phenotype depended on COX-2-mediated PGE(2) synthesis and correlated with increased expression of proliferation-associated Ki67 in epithelial cells. No changes in the expression of apoptosis-related Bcl-2, caspase 3, or p53 were observed. Hyperproliferation of the mammary gland epithelial cells was associated with increased aromatase mRNA levels in this tissue. The spontaneous pathologies bear analogies to the human breast with fibrocystic changes. Intriguingly, strong COX-2 expression was observed in fibrocystic changes, as compared to low expression in normal breast epithelium. These results show for the first time that aberrant COX-2 expression contributes to the development of fibrocystic changes (FC), indicating that COX-2 and COX-2-mediated PG synthesis represent potential targets for the therapy of this most frequent benign disorder of the human breast.
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PMID:Cystic duct dilatations and proliferative epithelial lesions in mouse mammary glands upon keratin 5 promoter-driven overexpression of cyclooxygenase-2. 1568 40

Beta-lapachone, the product of a tree Tabebuia avellanedae from South America, is known to exhibit various pharmacologic properties, the mechanisms of which are poorly understood. In the present study, we investigated further possible mechanisms by which beta-lapachone exerts its anti-proliferative action in cultured human prostate carcinoma DU145 cells. Exposure of DU145 cells to beta-lapachone resulted in growth inhibition and induction of apoptosis in a dose-dependent manner as measured by MTT assay, fluorescent microscopy, and flow-cytometry analysis. The increase in apoptosis was associated with a dose-dependent up-regulation in pro-apoptotic Bax expression, down-regulation of anti-apoptotic Bcl-2, and proteolytic activation of caspase-3 protease. We found beta-lapachone decreased the levels of cyclooxygenase (COX)-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with a decrease in prostaglandin E2 (PGE2) synthesis. Furthermore, beta-lapachone treatment markedly inhibited the activity of telomerase in a dose-dependent fashion. Additionally, the expression of human telomerase reverse transcriptase (hTERT), a main determinant of the telomerase enzymatic activity, was progressively down-regulated by beta-lapachone treatment. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of beta-lapachone.
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PMID:Down-regulation of cyclooxygenase-2 and telomerase activity by beta-lapachone in human prostate carcinoma cells. 1582 36

Previous studies have demonstrated that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a well-known DNA alkylating agent, induces G2/M arrest and apoptotic cell death in several human cancer cell lines. In the present study, we investigated the effects of MNNG on the growth of a U937 human leukemia cell model. The effects of this compound were also tested on cyclooxygenase (COX) activity. Treatment of U937 cells with MNNG resulted in the inhibition of viability and the induction of apoptosis in a concentration-dependent manner, which was associated with a dose-dependent upregulation in pro-apoptotic Bax protein, downregulation of anti-apoptotic Bcl-2 and Bcl-xL proteins, and proteolytic activation of caspase-3 protease. Furthermore, MNNG decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with inactivation of the reporter construct of a COX-2 promoter and decrease in prostaglandin E2 synthesis. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of MNNG.
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PMID:Induction of apoptosis and inhibition of cyclooxygenase-2 expression by N-methyl-N'-nitro-N-nitrosoguanidine in human leukemia cells. 1584 16


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