Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurotoxicant trimethyltin (TMT) induces massive neuronal loss in vivo in the hippocampus of rodents, accompanied by behavioral alterations. The present study investigates the pattern of cell death after in vivo administration of TMT to adult mice. In the granular cell layer of the Dentate Gyrus, TUNEL staining detected DNA fragmentation, and apoptotic bodies were also evident. In addition, a ladder pattern of internucleosomal DNA fragmentation was shown in agarose gel electrophoresis. We show that activated caspase-3, which is known to play a pivotal role in apoptotic processes, is clearly expressed by degenerating neurons. Inducible cyclooxygenase is also expressed at cytoplasmic level by degenerating granular neurons, suggesting that this enzyme may participate in TMT-induced neurodegeneration.
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PMID:Cyclooxygenase-2 and caspase 3 expression in trimethyltin-induced apoptosis in the mouse hippocampus. 1200 67

Cholangiocarcinoma is a rare but highly malignant primary hepatobiliary cancer with a high rate of mortality. Early diagnosis is difficult and current therapies are ineffective for the advanced disease. Although the molecular pathogenesis of cholangiocarcinoma is still poorly understood, there is increasing evidence to suggest that overexpression of the proto-oncogene-encoded receptor tyrosine kinase ERBB-2 together with upregulation of cyclooxygenase-2 (COX-2) may be an important feature of cholangiocarcinogenesis in both the human and the experimental rodent models. Evidence presented supports a strong positive correlation between ERBB-2 overexpression and cyclooxygenase upregulation in human cholangiocarcinogenesis. Combination drug targeting of ERBB-2 and of COX-2 was also found to act synergistically to suppress anchorage-independent growth and activate caspase-3 in cultured rat cholangiocarcinoma cells overexpressing both proteins. These findings suggest that aberrant expression of ERBB-2 and COX-2 is a common feature of human and rat cholangiocarcinomas and that targeting of both proteins may prove useful as a therapeutic strategy for this lethal cancer.
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PMID:Cyclooxygenase-2 and ERBB-2 in cholangiocarcinoma: potential therapeutic targets. 1236 Apr 23

Although the influence of selective cyclooxygenase (COX)-2 inhibitors on the proliferation of colon adenocarcinoma cells have been the subject of much investigation, relatively little research has compared the effects of different COX-2 inhibitors. Celecoxib strongly suppressed the proliferation of COX-2 expressing HT-29 cells at 10-40 microM. NS-398 and nimesulide also inhibited cell proliferation, whereas rofecoxib, meloxicam, and etodolac did not. Only celecoxib induced apoptosis of HT-29 cells, as detected on the basis of DNA fragmentation, TUNEL positivity, and caspase-3/7 activation. DNA fragmentation was also increasd in COX-2 non-expressing cell lines (SW-480 and HCT-116) by exposure to celecoxib for 6-24 h. All six COX-2 inhibitors suppressed the production of prostaglandin E(2) by HT-29 cells, suggesting that the pro-apoptotic effect of celecoxib was unrelated to inhibition of COX-2. Inactivation of Akt might explain the differential pro-apoptotic effect of these selective COX-2 inhibitors on colon adenocarcinoma cells.
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PMID:Selective cyclooxygenase-2 inhibitors show a differential ability to inhibit proliferation and induce apoptosis of colon adenocarcinoma cells. 1241 26

Renal mesangial cell apoptosis is a crucial repair mechanism in glomerular nephritis (GN). These cells express receptors to tumor necrosis factor alpha (TNFalpha), a cytokine with proapoptotic properties implicated in the resolution of GN. Progression to proliferative GN is accompanied by cyclooxygenase-mediated formation of prostaglandins and inefficient apoptosis of mesangial cells. The aims of this study were to quantify TNFalpha-mediated apoptosis in renal mesangial cells and to determine whether expression of the inducible form of cyclooxygenase, cylooxygenase-2 (COX-2), inhibits this apoptosis. By 24 h significant levels of apoptosis were induced by TNFalpha (100 ng/ml) or etoposide control (100 microm), as shown by phosphatidylserine externalization, caspase-3 activation, development of a sub-G(0)/G(1) region, and distinct chromatin condensation. Using adenoviral-mediated delivery of the COX-2 gene (AdCOX-2) apoptotic features were prevented from appearing in AdCOX-2 cells treated with TNFalpha, whereas etoposide-treated AdCOX-2 cells were not protected. Furthermore, COX-2 expression, induced by the vasoconstrictor peptide ET-1 or the cytokine interleukin-1beta also inhibited TNFalpha-mediated but not etoposide-mediated apoptosis, to an extent, similar to adenoviral COX-2 infection. Selective COX-2 inhibition by NS-398 restored TNFalpha-mediated apoptosis. Prostaglandin (PG) E(2) and PGI(2) were shown to be the major prostaglandin metabolites in AdCOX-2 cells. The addition of PGE(2) and PGI(2) protected against TNFalpha-mediated apoptosis. These results demonstrate COX-2 anti-apoptotic activity via a death receptor route and suggest that selective COX-2 inhibition may augment TNFalpha apoptosis in chronic inflammatory conditions.
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PMID:Cyclooxygenase-2 inhibits tumor necrosis factor alpha-mediated apoptosis in renal glomerular mesangial cells. 1251 56

Nitric oxide (NO) causes apoptosis and dedifferentiation of articular chondrocytes by the modulation of extracellular signal-regulated kinase (ERK), p38 kinase, and protein kinase C (PKC) alpha and -zeta. In this study, we investigated the effects and mechanisms of non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, ketoprofen, ibuprofen, sulindac sulfide, and flurbiprofen, in NO-induced apoptosis and dedifferentiation of articular chondrocytes. We found that all of the examined NSAIDs inhibited apoptosis and dedifferentiation. NO production in chondrocytes caused activation of ERK-1/2 and p38 kinase, which oppositely regulate apoptosis and dedifferentiation. NO production also caused inhibition of PKCalpha and -zeta independent of and dependent on, respectively, p38 kinase, which is required for apoptosis and dedifferentiation. Among the signaling molecules modulated by NO, NSAIDs blocked NO-induced activation of p38 kinase, potentiated ERK activation, and blocked inhibition of PKCalpha and -zeta. NSAIDs also inhibited some of the apoptotic signaling that is downstream of p38 kinase and PKC, such as NFkappaB activation, p53 accumulation, and caspase-3 activation. The inhibitory effects of NSAIDs on apoptosis and dedifferentiation were independent of the inhibition of cyclooxygenase (COX)-2 and prostaglandin E(2) (PGE(2)) production, as evidenced by the observation that specific inhibition of COX-2 activity and PGE(2) production or exogenous PGE(2) did not affect NO-induced apoptosis and dedifferentiation. Taken together, our results indicate that NSAIDs block NO-induced apoptosis and dedifferentiation of articular chondrocytes by the modulation of ERK, p38 kinase, and PKCalpha and -zeta in a manner independent of their ability to inhibit COX-2 and PGE(2) production.
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PMID:Non-steroidal anti-inflammatory drugs inhibit nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes independent of cyclooxygenase activity. 1258 66

Nitric oxide (NO) in articular chondrocytes regulates differentiation, survival, and inflammatory responses by modulating ERK-1 and -2, p38 kinase, and protein kinase C (PKC) alpha and zeta. In this study, we investigated the effects of the actin cytoskeletal architecture on NO-induced dedifferentiation, apoptosis, cyclooxygenase (COX)-2 expression, and prostaglandin E2 production in articular chondrocytes, with a focus on ERK-1/-2, p38 kinase, and PKC signaling. Disruption of the actin cytoskeleton by cytochalasin D (CD) inhibited NO-induced apoptosis, dedifferentiation, COX-2 expression, and prostaglandin E2 production in chondrocytes cultured on plastic or during cartilage explants culture. CD treatment did not affect ERK-1/-2 activation but blocked the signaling events necessary for NO-induced dedifferentiation, apoptosis, and COX-2 expression such as activation of p38 kinase and inhibition of PKCalpha and -zeta. CD also suppressed activation of downstream signaling of p38 kinase and PKC, such as NF-kappaB activation, p53 accumulation, and caspase-3 activation, which are necessary for NO-induced apoptosis. NO production in articular chondrocytes caused down-regulation of phosphatidylinositol (PI) 3-kinase and Akt activities. The down-regulation of PI 3-kinase and Akt was blocked by CD treatment, and the CD effects on apoptosis, p38 kinase, and PKCalpha and -zeta were abolished by the inhibition of PI 3-kinase with LY294002. Our results collectively indicate that the actin cytoskeleton mediates NO-induced regulatory effects in chondrocytes by modulating down-regulation of PI 3-kinase and Akt, activation of p38 kinase, and inhibition of PKCalpha and -zeta
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PMID:Actin cytoskeletal architecture regulates nitric oxide-induced apoptosis, dedifferentiation, and cyclooxygenase-2 expression in articular chondrocytes via mitogen-activated protein kinase and protein kinase C pathways. 1290 84

Transforming growth factor-beta (TGF-beta) induces an oxidative stress process in hepatocytes that mediates its apoptotic activity. To determine the cellular source of the early reactive oxygen species (ROS) generated by fetal rat hepatocytes in response to TGF-beta, we used inhibitors that block different ROS-producing systems. Diphenyleneiodonium, which inhibits NADPH oxidase and other flavoproteins, completely blocked the increase in ROS induced by TGF-beta, coincidently with an impairment of caspase-3 activation and cell death. Rotenone, an inhibitor of the NADH dehydrogenase in mitochondrial complex I, attenuated, but did not completely inhibit, ROS-production, caspase activation, and cell death mediated by TGF-beta. No significant protection was observed with inhibitors of other ROS-producing systems, such as cytochrome P450 (metyrapone), cyclooxygenase (indomethacin), and xanthine oxidase (allopurinol). Additional experiments have indicated that two different mechanisms could be involved in the early ROS production by TGF-beta. First, an inducible (cycloheximide-inhibited) NADPH oxidase-like system could account for the extramitochondrial production of ROS. Second, TGF-beta could increase ROS by a rapid downregulation of antioxidant genes. In particular, intramitochondrial ROS would increase by depletion of MnSOD. Finally, glutathione depletion is a late event and it would be more the consequence than the cause of the increase in ROS induced by TGF-beta.
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PMID:Source of early reactive oxygen species in the apoptosis induced by transforming growth factor-beta in fetal rat hepatocytes. 1473 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

Wikyungtang, an oriental herbal formulation, has been known to exert anti-inflammatory and anti-tumoral activity. However, its molecular mechanism of action is not understood. The purpose of the present study was to examine the effect of the water extract of Wikyungtang (WKT) on the growth of A549 human lung cancer cells. Treatment with WKT resulted in a dose-dependent growth inhibition coupled with the characteristic morphological features of apoptosis. Apoptosis-inducing concentrations of WKT induced caspase-3 and caspase-9 activation accompanied by proteolytic degradation of poly(ADP-ribose)-polymerase and phospholipase C-gamma1. In addition, WKT-induced apoptosis in A549 cells was associated with a decreased expression of the anti-apototic Bcl-XL expression. WKT treatment also inhibited the expression of cyclooxygenase (COX)-2 and the accumulation of prostaglandin E2 without significant changes in the levels of COX-1. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of WKT.
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PMID:Wikyungtang inhibits proliferation of A549 human lung cancer cells via inducing apoptosis and suppressing cyclooxygenase-2 activity. 1501 Aug 84

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


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