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)

Interferon alpha (IFNalpha) is used to treat patients with advanced renal cell carcinoma (RCC) despite limited clinical benefit. IFNalpha can induce Fas receptor-mediated apoptosis by direct activation of pro-caspase-8 followed by activation of caspase-3. Alternative, indirect activation of caspase-3 via mitochondrial release of cytochrome c can occur and may explain the rescue from Fas-activated cell death by the antiapoptotic members of the Bcl-2 family. In this study, we examined G3139, a novel antisense compound targeting Bcl-2, in combination with IFNalpha. Human RCC lines (SK-RC-44 and SK-RC-07) were treated with IFNalpha, G3139 or a combination of the two. Fas-mediated cytotoxicity was induced by anti-Fas mAb, CH11. An analysis of Bcl-2, Fas and the cleavage of PARP was performed. IFNalpha induced Fas and Bcl-2 in SK-RC-44 and SK-RC-07. IFNalpha sensitised SK-RC-44 to anti-Fas and induced PARP cleavage confirming that IFNalpha has a cytotoxic effect on RCC lines by induction of the Fas antigen. Cytotoxicity was not evident in SK-RC-07 cells treated with IFNalpha. G3139 induced a specific downregulation of Bcl-2 in SK-RC-07 cells, which were then sensitised to anti-Fas after treatment with IFNalpha. Taken together, these results suggest that Fas-dependent pathways as well as alternative pathways, which can be inhibited by Bcl-2, exist in renal cell carcinoma. G3139 in combination with IFNalpha is a potential therapy in patients with metastatic renal cell carcinoma.
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PMID:Downregulation of Bcl-2 sensitises interferon-resistant renal cancer cells to Fas. 1518 8

BPR0Y007, a bis-benzylidenecyclopentanone derivative (2,5-bis- (4-hydroxy-3-methoxybenzylidene) cyclopentanone), was identified in our laboratory as a novel antineoplastic agent with a broad spectrum of antitumor activity against many human cancer cells. A previous study showed that BPR0Y007 inhibited DNA topoisomerase I (Top 1) activity and prevented tubulin polymerization. Notably, no cross-resistance with BPR0Y007 was observed in camptothecin-, VP-16- or vincristine-resistant cell lines. In this study, we further investigated the cellular and molecular events underlying the antitumoral function of this compound in human oral epidermoid carcinoma KB cells, focusing on the early cytotoxic effect. Treatment of KB cells with BPR0Y007-induced G(2)/M phase arrest followed by sub-G(1) phase accumulation. Annexin-V-propidium iodide (PI) binding assay and DNA fragmentation assay further indicated that BPR0Y007-induced cell death proceeded through an apoptotic pathway as opposed to via necrosis. This compound produced a time-dependent activation of caspases-3 and -8, however, another caspase-3 initiator, caspase-9, was only marginally activated at later time point. We further demonstrated that the activation of the caspases cascade and nuclear fragmentation was not associated with inactivated Bcl-2 and perturbed mitochondrial membrane potential by BPR0Y007. The finding that BPR0Y007-induced apoptosis through a membrane-mediated mechanism was supported by up-regulated expression of Fas (CD95/APO-1), but not Fas-L. Furthermore, up-regulation of p53 and its affected gene, MDM2, in KB cells was found after BPR0Y007 exposure. Overall, our results demonstrated that the BPR0Y007 could induce an early cytotoxic apoptosis through a caspase-8-dependent but mitochondrial-caspase-9 independent pathway, and involving upregulation of p53.
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PMID:A novel bis-benzylidenecyclopentanone derivative, BPR0Y007, inducing a rapid caspase activation involving upregulation of Fas (CD95/APO-1) and wild-type p53 in human oral epidermoid carcinoma cells. 1519 1

Luteinizing hormone-releasing hormone (LHRH) and its receptor are frequently expressed in human ovarian and endometrial cancers and are part of an autocrine mechanism of growth control. We have previously shown that the LHRH analog Triptorelin induces activation of nucleus factor kappa B (NFkappaB) and reduces apoptosis induced by doxorubicin in human ovarian cancer cells EFO-21 and EFO-27. The present study was performed to investigate the anti-apoptotic effects of LHRH analogs on apoptosis induced by doxorubicin, UV-light and ligation of CD95 in human endometrial and ovarian cancer cells. We further investigated the interaction of the LHRH system with the apoptotic pathway focusing on the effector-protease caspase 3. Doxorubicin (100 nM) induced apoptosis in the LHRH-receptor-positive human endometrial cancer cell line Ishikawa and in the human ovarian cancer cell lines EFO-21 and NIH:OVCAR-3. Pretreatment for 24 h with native LHRH, the LHRH agonist Triptorelin or the LHRH antagonist Cetrorelix (100 nM) significantly reduced apoptosis induced by doxorubicin in these cells. In EFO-21 cells pretreatment with 100 nM Triptorelin also reduced UV-light-induced apoptosis from 76% to 62.7% (p<0.01). EFO-21 cells express CD95. Cross-linking of CD95 with monoclonal antibody anti-APO-1 (500 ng/ml) increased apoptosis from spontaneous rate to 10.3% to 38.3% in EFO-21 cells (p<0.001). Pre-treatment with Triptorelin did not reduce CD95-mediated apoptosis in these cells. LHRH analogs protect human endometrial and ovarian cancer cells from DNA-replication-dependent cytotoxic agent and UV-light-induced apoptosis, but not from CD95-mediated apoptosis.
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PMID:Luteinizing hormone-releasing hormone (LHRH) inhibits apoptosis induced by cytotoxic agent and UV-light but not apoptosis mediated through CD95 in human ovarian and endometrial cancer cells. 1527 47

Progesterone is suggested to be a suppressor of apoptosis in bovine luteal cells. Fas antigen (Fas) is a cell surface receptor that triggers apoptosis in sensitive cells. Furthermore, apoptosis is known to be controlled by the bcl-2 gene/protein family and caspases. This study was undertaken to determine whether intraluteal progesterone (P4) is involved in Fas L-mediated luteal cell death in the bovine corpus luteum (CL) in vitro. Moreover, we studied whether an antagonist of P4 influences gene expression of the bcl-2 family and caspase-3 and the activity of caspase-3 in the bovine CL. Luteal cells obtained from the cows in the midluteal phase of the estrous cycle (Days 8-12 of the cycle) were exposed to a specific P4 antagonist (onapristone [OP], 10(-4) M) with or without 100 ng/ml Fas L. Although Fas L alone did not show a cytotoxic effect, treatment of the cells with OP alone or in combination with Fas L resulted in killing of 30% and 45% of the cells, respectively (P <0.05). DNA fragmentation was observed in the cells treated with Fas L in the presence of OP. The inhibition of P4 action by OP increased the expression of Fas mRNA (P <0.01); however, it did not affect bax or bcl-2 mRNA expression (P >0.05). Moreover, OP stimulated expression of caspase-3 mRNA (P <0.01). The overall results indirectly show that intraluteal P4 suppresses apoptosis in bovine luteal cells through the inhibition of Fas and caspase-3 mRNA expression and inhibition of caspase-3 activation.
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PMID:Progesterone is a suppressor of apoptosis in bovine luteal cells. 1532 28

More than 99% of follicles undergo a degenerative process known as "atresia", in mammalian ovaries, and only a few follicles ovulate during ovarian follicular development. We have investigated the molecular mechanism of selective follicular atresia in mammalian ovaries, and have reported that follicular selection dominantly depends on granulosa cell apoptosis. However, we have little knowledge of the molecular mechanisms that control apoptotic cell death in granulosa cells during follicle selection. To date, at least five cell death ligand-receptor systems [tumor necrosis factor (TNF)alpha and receptors, Fas (also called APO-1/CD95) ligand and receptors, TNF-related apoptosis-inducing ligand (TRAIL; also called APO-2) and receptors, APO-3 ligand and receptors, and PFG-5 ligand and receptors] have been reported in granulosa cells of porcine ovaries. Some cell death ligand-receptor systems have "decoy" receptors, which act as inhibitors of cell death ligand-induced apoptosis in granulosa cells. Moreover, we showed that the porcine granulosa cell is a type II apoptotic cell, which has the mitochondrion-dependent apoptosis-signaling pathway. Briefly, the cell death receptor-mediated apoptosis signaling pathway in granulosa cells has been suggested to be as follows. (1) A cell death ligand binds to the extracellular domain of a cell death receptor, which contains an intracellular death domain (DD). (2) The intracellular DD of the cell death receptor interacts with the DD of the adaptor protein (Fas-associated death domain: FADD) through a homophilic DD interaction. (3) FADD activates an initiator caspase (procaspase-8; also called FLICE), which is a bipartite molecule, containing an N-terminal death effector domain (DED) and a C-terminal DD. (4) Procaspase-8 begins auto-proteolytic cleavage and activation. (5) The auto-activated caspase-8 cleaves Bid protein. (6) The truncated Bid releases cytochrome c from mitochondrion. (7) Cytochrome c and ATP-dependent oligimerization of apoptotic protease-activating factor-1 (Apaf-1) allows recruitment of procaspase-9 into the apoptosome complex. Activation of procaspase-9 is mediated by means of a conformational change. (8) The activated caspase-9 cleaves downstream effector caspases (caspase-3). (9) Finally, apoptosis is induced. Recently, we found two intracellular inhibitor proteins [cellular FLICE-like inhibitory protein short form (cFLIPS) and long form (cFLIPL)], which were strongly expressed in granulosa cells, and they may act as anti-apoptotic/survival factors. Further in vivo and in vitro studies will elucidate the largely unknown molecular mechanisms, e. g. which cell death ligand-receptor system is the dominant factor controlling the granulosa cell apoptosis of selective follicular atresia in mammalian ovaries. If we could elucidate the molecular mechanism of granulosa cell apoptosis (follicular selection), we could accurately diagnose the healthy ovulating follicles and precisely evaluate the oocyte quality. We hope that the mechanism will be clarified and lead to an integrated understanding of the regulation mechanism.
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PMID:Regulation mechanism of selective atresia in porcine follicles: regulation of granulosa cell apoptosis during atresia. 1551 56

Apigenin is a widely distributed plant flavonoid and was proposed as an antitumor agent. In this study, we reported for the first time that apigenin inhibited the growth of human cervical carcinoma cells (HeLa) and through apoptotic pathway. The results showed that apigenin significantly decreased the viability of HeLa cells at 37-74 microM and the IC50 value was 35.89 microM. Apigenin-induced apoptosis in HeLa cells was confirmed by DNA fragmentation assay and induction of sub-G1 phase by flow cytometry. Apigenin-treated HeLa cells were arrested at G1 phase, which was associated with a marked increment of the expression of p21/WAF1 protein. The induction of p21/WAF1 appeared to be transcriptionally upregulated and was p53-dependent. In addition, apigenin induced Fas/APO-1 and caspase-3 expression which were also correlated with apoptosis. Apigenin decreased in the protein expression of Bcl-2 protein, which is an anti-apoptotic factor. The conclusion of this study is the apigenin induced p53 expression which caused cell cycle arrest and apoptosis. These findings suggest that apigenin has strong potential for development as an agent for preventing cervical cancer.
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PMID:Apigenin induced apoptosis through p53-dependent pathway in human cervical carcinoma cells. 1567 Jun 16

The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was mediated by a phosphatidylinositol 3-kinase (PI 3-kinase)-Akt/protein kinase B (PKB)-dependent expression of lifeguard (LFG)/neuronal membrane protein 35. Reduction of endogenous LFG expression by antisense oligonucleotides or small interfering RNA lead to increased sensitivity of CGNs to FasL-induced cell death and caspase-8 cleavage. The inhibition of PI 3-kinase activity sensitized CGNs to FasL-induced caspase-8 and caspase-3 processing and caspase-dependent fodrin cleavage. Pharmacological inhibition of PI 3-kinase, overexpression of the inhibitory protein IkappaB, or cotransfection of an LFG reporter plasmid with dominant-negative Akt/PKB inhibited LFG reporter activity, whereas overexpression of constitutively active Akt/PKB increased LFG reporter activity. Overexpression of LFG in CGNs interfered with the sensitization to FasL by PI 3-kinase inhibitors. In contrast to CGNs, 12 glioma cell lines, which are sensitive to FasL, did not express LFG. Gene transfer of LFG into these FasL-susceptible glioma cells protected against FasL-induced apoptosis. These results demonstrate that LFG mediated the FasL resistance of CGNs and that, under certain circumstances, e.g., inhibition of the PI 3-kinase-Akt/PKB pathway, CGNs were sensitized to FasL.
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PMID:FasL (CD95L/APO-1L) resistance of neurons mediated by phosphatidylinositol 3-kinase-Akt/protein kinase B-dependent expression of lifeguard/neuronal membrane protein 35. 1603 86

The anomalous fruit extract of Gleditsia sinensis (GSE) was shown to possess anticancer potential on various solid tumour and leukaemia cell lines in vitro. We have recently demonstrated that the mitochondrial-dependent apoptotic pathway including mitochondrial membrane potential depolarization, changes in the level of reactive oxygen species and activation of caspase 3 were recruited in GSE-induced apoptosis. Whether receptor-dependent APO-1/Fas apoptotic pathway is also involved remains uncertain. Using two solid tumour cell lines, the HepG2 hepatoblastoma carcinoma cells and MDA-MB231 breast cancer cells, we demonstrated that the Fas ligand and Fas receptor protein levels did not have significant variation after GSE incubation. Caspase 8 activity increased only weakly when compared with that of caspase 3. The chrymotrypsin-like activity of proteasome was partially inhibited up to 30-40% when compared with the untreated control. Taken together, we believe that GSE- mediated apoptosis on HepG2 and MDA-MB231 carcinoma cells is mainly dictated by the mitochondrial-dependent pathway while inhibition of proteasome activity may also be involved in GSE-induced apoptosis.
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PMID:Inhibition of proteasome activity in Gleditsia sinensis fruit extract-mediated apoptosis on human carcinoma cells. 1621 Dec 65

We have recently demonstrated the antiproliferative and apoptotic activities of herbal traditional Chinese medicines, including the analomous fruit extract of Gleditsia sinensis, the fresh juice of Scutellaria barbata and the warmed water extract of Radix Sophorae Tonkinensis on a series of human carcinoma cells. Here, we further report the potential anti-cancer activity of the warmed water extract of Brucea javanica (BJE). Four cancer cell lines, including A549 non-small cell lung cancer, Hep3B hepatocellular carcinoma, MDA-MB231 breast cancer and SLMT-1 oesophageal squamous cell carcinoma, were incubated with BJE and strong apoptotic induction was observed under inverted microscopic investigation for all of the four cell lines tested. Using the MDA-MB231 breast cancer cell line as an experimental model, additional analyses supported the hypothesis that the mitochondrial membrane potential depolarization pathway was induced by BJE. The APO-1/Fas receptor death induction pathway was not activated under the influence of BJE, as studied by staining with Fas ligand and Fas receptor specific antibodies. Accordingly, only weak activation of caspase 8 was observed upon BJE treatment. On the other hand, caspase 3 activity was stimulated up to five-fold in BJE-treated cells compared to untreated controls. Oligonucleosomal DNA fragmentation formation was detected by labelling the nucleic acid ladders with TdT-mediated dUTP nick end labelling. Collectively, BJE-induced cancer cell death proceeds through a mitochondrial dependent pathway associated with caspase 3 activation.
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PMID:Antiproliferative and apoptosis-inducing activity of Brucea javanica extract on human carcinoma cells. 1627

Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole), one of the simplest naturally occurring alkaloids, was isolated from the leaves of the evergreen tree Ochrosia elliptica Labill (Apocynaceae). Here, we reported that ellipticine inhibited the cell growth of human hepatocellular carcinoma cell line HepG2 and provided molecular understanding of this effect. The XTT assay results showed that ellipticine decreased the cell viability of HepG2 cells in a dose- and time-dependent manner, and the IC50 value was 4.1 microM. Furthermore, apoptosis induction by ellipticine in HepG2 cells was verified by the appearance of DNA fragmentation and annexin V-FITC/propidium iodide (PI) staining assay. Ellipticine treatment was found to result in the upregulation of p53, Fas/APO-1 receptor and Fas ligand. Besides, ellipticine also initiated mitochondrial apoptotic pathway through regulation of Bcl-2 family proteins expression, alteration of mitochondrial membrane potential (DeltaPsim), and activation of caspase-9 and caspase-3. Taken together, ellipticine decreased the cell growth and induced apoptosis in HepG2 cell.
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PMID:Ellipticine induces apoptosis through p53-dependent pathway in human hepatocellular carcinoma HepG2 cells. 1633 42


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