UNIPROT:P42574 - FACTA Search

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

The presence of prostaglandins (PGs) has been demonstrated in the processes of carcinogenesis and inflammation. In the present study, we found that 12-o-tetradecanoylphorbol 13-acetate (TPA) induced cyclooxygenase 2 (COX-2), but not COX-1, protein expression in HL-60 cells, and the addition of arachidonic acid (AA) in the presence or absence of TPA significantly reduced the viability of HL-60 cells, an effect that was blocked by adding the COX inhibitors, NS398 and aspirin. The AA metabolites, PGD(2) and PGJ(2), but not PGE(2) or PGF(2alpha), reduced the viability of the human HL60 and Jurkat leukemia cells according to the MTT assay and LDH release assay. Apoptotic characteristics including DNA fragmentation, apoptotic bodies, and hypodiploid cells were observed in PGD(2)- and PGJ(2)-treated leukemia cells. A dose- and time-dependent induction of caspase 3 protein procession, and PARP and D4-GDI protein cleavage with activation of caspase 3, but not caspase 1, enzyme activity was detected in HL-60 cells treated with PGD(2) or PGJ(2). Additionally, DNA ladders induced by PGD(2) and PGJ(2) were significantly inhibited by the caspase 3 peptidyl inhibitor, Ac-DEVD-FMK, but not by the caspase 1 peptidyl inhibitor, Ac-YVAD-FMK, in accordance with the blocking of caspase 3, PARP, and D4-GDI protein procession. An increase in intracellular peroxide levels by PGD(2) and PGJ(2) was identified by the DCHF-DA assay, and anti-oxidant N-acetyl cysteine (NAC), mannitol (MAN), and tiron significantly inhibited cell death induced by PGD(2) and PGJ(2) by reducing reactive oxygen species (ROS) production. The PGJ(2) metabolites, 15-deoxy-Delta(12,14)-PGJ(2) and Delta(12)-PGJ(2), exhibited effective apoptosis-inducing activity in HL-60 cells through ROS production via activation of the caspase 3 cascade. The proliferator-activated receptor-gamma (PPAR-gamma) agonists, rosiglitazone (RO), troglitazone (TR), and ciglitazone (CI), induced apoptosis in cells which was blocked by the addition of the PPAR-gamma antagonists, GW9662 and BADGE, via blocking of caspase 3 and PARP cleavage. However, neither GW9662 nor BADGE showed any protective effect on PGD(2)- and PGJ(2)-induced apoptosis. A differential apoptotic effect of PGs through ROS production, followed by activation of the caspase 3 cascade, was demonstrated.
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PMID:Prostaglandin D(2) and J(2) induce apoptosis in human leukemia cells via activation of the caspase 3 cascade and production of reactive oxygen species. 1584 42

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

Although histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in malignancy, how they exert their effect on human non-small cell lung cancer cells is as yet unclear. This study was undertaken to investigate the underlying mechanism of an HDAC inhibitor, Trichostatin A (TSA), -induced apoptosis in a human lung carcinoma cell line A549. The effects of this compound were also tested on cyclooxygenase (COX) activity. Treatment of A549 cells to TSA resulted in the inhibition of viability and the induction of apoptosis in a concentration-dependent manner, which could be proved by trypan blue counts, DAPI staining, agarose gel electrophoresis and flow cytometry analysis. Apoptosis of A549 cells by TSA was associated with a down-regulation of anti-apoptotic Bcl-2 protein and an up-regulation of pro-apoptotic Bax protein. TSA treatment induced the proteolytic activation of caspase-3 and caspase-9, and a concomitant degradation of poly(ADP-ribose)-polymerase protein. Furthermore, TSA decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with an inhibition in prostaglandin E2 synthesis. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of TSA.
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PMID:Induction of apoptosis by trichostatin A, a histone deacetylase inhibitor, is associated with inhibition of cyclooxygenase-2 activity in human non-small cell lung cancer cells. 1601 Apr 30

Chan Su is a traditional Chinese medicine prepared from the dried white secretion of the auricular and skin glands of toads, and has been used as an Oriental drug. However, little is known about the effect of Chan Su on the growth of human cancer cells. This study was undertaken to investigate the underlying mechanism of Chan Su-induced apoptosis in a human bladder carcinoma cell line, T24. The effects of this compound were also tested on cyclooxygenase (COX) activity. Treatment of T24 cells with Chan Su resulted in the inhibition of viability and induction of apoptosis in a concentration-dependent manner, which was proved by trypan blue counts, DAPI staining, agarose gel electrophoresis and flow cytometric analysis. Apoptosis of T24 cells by Chan Su was associated with a down-regulation of anti-apoptotic Bcl-2 and Bcl-X(S/L) expression and an up-regulation of pro-apoptotic Bax expression. Chan Su treatment induced the proteolytic activation of caspase-3 and caspase-9, and a concomitant degradation of poly(ADP-ribose)-polymerase and beta-catenin protein. Furthermore, Chan Su decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with an inhibition in prostaglandin E(2) synthesis. Taken together, these findings partially provide novel insights into the possible molecular mechanisms of the anti-cancer activity of Chan Su.
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PMID:Induction of apoptosis by Chan Su, a traditional Chinese medicine, in human bladder carcinoma T24 cells. 1601 33

A decisive role in cancer development has been attributed to cyclooxygenase-2 (COX-2) activity, but the significance of COX-2 inhibitors in cancer treatment still needs to be thoroughly investigated. We studied the influence of meloxicam, a non-steroidal antiinflammatory drug with preferential inhibitory effects on COX-2 compared to COX-1, on canine osteosarcoma (D-17) cells. We demonstrated that D-17 cells expressed mRNA and COX-2 protein. Treatment with meloxicam induced a time- and dose-dependent inhibition of cellular growth. To determine if apoptosis plays a role in meloxicam-induced cell death, we performed agarose gel electrophoresis and found a DNA-ladder pattern, typically seen in apoptosis, as well as early apoptotic changes by Annexin V tests. Furthermore, electron microscopy revealed ultrastructural alterations typical of apoptosis. Quantification of apoptotic cells by immunohistochemical staining of caspase 3 confirmed the results. However, further studies with meloxicam are necessary to assess its potential use for treatment of osteosarcomas in dogs.
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PMID:Antineoplastic effect of the cyclooxygenase inhibitor meloxicam on canine osteosarcoma cells. 1618 28

Cyclooxygenase (COX) inhibitors have suppressive effects on several types of cancer cells including prostate cancer. In this study, we considered the potential COX-inhibitory activity of a unique anti-inflammatory herbal preparation (Zyflamend; New Chapter, Inc., Brattleboro, VT) and analyzed its effects on the human prostate cancer cell line LNCaP. COX inhibitory activity of Zyflamend was determined by a spectrophotometric-based assay using purified ovine COX-1 and COX-2 enzymes. Effects of Zyflamend on LNCaP cell growth and apoptosis in vitro were assessed by cell counting, Western blot detection of poly ADP-ribose polymerase (PARP) cleavage, and measurement of caspase-3 activity in treated and control cell extracts. Western blotting techniques were conducted to determine the effects of this herbal preparation on the expression of the cell signaling proteins, p21, androgen receptor (AR), phospho-protein kinase C (pPKC)(alpha/beta), and phospho (p)Stat3. The phospohorylation status of several signal transduction phosphoproteins was profiled using a high-throughput phosphoprotein screening assay in treated cells and compared to controls. Zyflamend dramatically decreased COX-1 and COX-2 enzymatic activity. Elevated p21 expression coincided with attenuated cell growth following treatment of LNCaP cells with Zyflamend. PARP cleavage fragments were evident, and caspase-3 activity was upregulated over the control indicating the ability of Zyflamend to induce apoptosis of these cells. Androgen receptor expression levels declined by 40%, and decreases were observed in the active forms of Stat3 and PKC(alpha/beta) in Zyflamend-treated LNCaP cells. Zyflamend inhibited both COX-1 and COX-2 enzymatic activities, suppressed cell growth, and induced apoptosis in LNCaP cells. However, our data suggests that the effects are likely due to COX-independent mechanisms potentially involving enhanced expression of p21 and reduced expression of AR, pStat3, and pPKC(alpha/beta).
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PMID:Zyflamend, a unique herbal preparation with nonselective COX inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression. 1620 51

Two isoforms of cyclooxygenase (COX) are known, and to date most studies have implicated COX-2 in the development and progression of various human cancers. Increasing evidence suggests that COX-1 may also play a similar role. Indeed, we have recently observed that the dual COX-1/COX-2 inhibitor indomethacin induces apoptosis in human hepatocellular carcinoma (HCC) cell lines more effectively than the selective COX-2 inhibitors, possibly implicating COX-1 in HCC. In this study we investigated the expression of COX-1 in non-tumor and malignant human liver tissues, as well as the effects of the highly selective COX-1 inhibitor SC-560 on cell growth and apoptosis in human HCC cell lines. Expression of COX-1 was detected in nearly all the samples assayed, although with a high variability between non-tumoral (NT) and malignant tissues. The percentage of COX-1 positive cells was significantly higher in the NT tissues than in the tumors (p<0.0001). In well-differentiated HCC COX-1 expression was significantly higher than in the poorly-differentiated tissues (p<0.05). SC-560 showed a dose- and time-dependent inhibitory effect on HCC cell growth. The combination of the COX-1 inhibitor with nimesulide and CAY10404, two selective COX-2 inhibitors, resulted in additive effects on cell growth inhibition. SC-560 also inhibited colony formation in soft agar and induced apoptosis in HCC cells in a dose-dependent manner. Moreover, SC-560 decreased the levels of the anti-apoptotic proteins survivin and XIAP and activated caspase-3 and -7 in a dose- and time-dependent fashion. In conclusion, we report for the first time that the selective COX-1 inhibitor SC-560 exhibits anti-tumor and apoptotic effects in human HCC cells. Overall, our previous and present results suggest that both COX-1 and COX-2 inhibitors may have potential therapeutic implications in HCC patients.
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PMID:The selective cyclooxygenase-1 inhibitor SC-560 suppresses cell proliferation and induces apoptosis in human hepatocellular carcinoma cells. 1639 22

The causes of, and predisposing conditions for, increased congenital anomalies in embryos of experimental diabetic gestation are not fully identified. In the present study, some possible factors involved in diabetes-induced embryopathy are explored. The concentration of PGE2, the gene expression of cyclooxygenases (COX-1 and COX-2) and level of apoptosis (measured by caspase-3 activity) are assessed during organogenesis in the embryos of streptozotocin-induced diabetic rats. The concentrations of PGE2 in the embryos of diabetic rats were lower than controls, with the lowest values in malformed embryos and their associated membranes (yolk sacs). The pattern of change in PGE2 was similar in the embryos of the control and diabetic groups, which showed a steady decline between days 9 and 11 of gestation. These changes in PGE2 were accompanied by a small decrease in COX-1 expression in all embryos and associated membranes during the same gestational period. Expression of COX-2, which was below normal in diabetic embryos, decreased between days 9 and 11 of gestation in all groups. In the membranes of non-malformed embryos, COX-2 expression peaked on day 10 of gestation. It was found that there was little or no detectable COX-2 expression in the membranes of malformed embryos on day 9 of gestation and although its expression was detectable on the following days it was much lower than in the other groups. Caspase-3 activity increased substantially between days 9 and 11 of gestation. Embryos from the experimentally diabetic group showed higher activity than did controls, with the largest increases in the malformed embryos. It would appear that COX-2 expression and PGE2 concentration (in both embryo and associated membranes) play a significant role in organ formation. The data presented here suggest that an unhealthy placenta may be instrumental in the development of malformed embryos.
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PMID:Embryopathy in experimental diabetic gestation: assessment of PGE2 level, gene expression of cyclooxygenases and apoptosis. 1641 74

Growing evidence indicates that inducible cyclooxygenase-2 (COX-2) is involved in the pathogenesis of inflammatory disorders and various types of cancer. Endothelial progenitor cells recruited from the bone marrow have been shown to be involved in the formation of new vessels in malignancies and discussed for being a key point in tumour progression and metastasis. However, until now, nothing is known about an interaction between COX and endothelial progenitor cells (EPC). Expression of COX-1 and COX-2 was detected by semiquantitative RT-PCR and Western blot. Proliferation kinetics, cell cycle distribution and rate of apoptosis were analysed by MTT test and FACS analysis. Further analyses revealed an implication of Akt phosphorylation and caspase-3 activation. Both COX-1 and COX-2 expression can be found in bone-marrow-derived endothelial progenitor cells in vitro. COX-2 inhibition leads to a significant reduction in proliferation of endothelial progenitor cells by an increase in apoptosis and cell cycle arrest. COX-2 inhibition leads further to an increased cleavage of caspase-3 protein and inversely to inhibition of Akt activation. Highly proliferating endothelial progenitor cells can be targeted by selective COX-2 inhibition in vitro. These results indicate that upcoming therapy strategies in cancer patients targeting COX-2 may be effective in inhibiting tumour vasculogenesis as well as angiogenic processes.
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PMID:Inhibition of cyclooxygenase (COX)-2 affects endothelial progenitor cell proliferation. 1689 39

Adipocytes can function as endocrine cells secreting a variety of adipocytokines including tumor necrosis factor (TNF)-alpha. Treatment of cultured mouse 3T3-L1 preadipocytes with TNF-alpha induced apoptosis, as was evident from increases in nuclear condensation and caspase-3 activity, but differentiated adipocytes during the maturation phase showed resistance to apoptosis by TNF-alpha. Antioxidants effectively reduced TNF-alpha-induced apoptosis in preadipocytes, indicating the involvement of reactive oxygen species. Exposure of preadipocytes to calcium ionophore A23187 reduced TNF-alpha-induced apoptosis, which was accompanied by increased production of prostaglandins (PGs) E2 and PGF 2alpha. TNF-alpha preferentially promoted gene expression of cyclooxygenase (COX)-2 without affecting that of COX-1. Consistently, NS-398, a COX-2 inhibitor, stimulated TNF-alpha-induced apoptosis, which was reversed by exogenous PGE2 and PGF 2alpha. These results indicate that endogenous PGE2 and PGF 2alpha synthesized by preadipocytes through the induction of COX-2 can serve as anti-apoptotic factors against apoptosis by TNF-alpha.
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PMID:Endogenous prostaglandins E2 and F 2alpha serve as an anti-apoptotic factor against apoptosis induced by tumor necrosis factor-alpha in mouse 3T3-L1 preadipocytes. 1696 Mar 84

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