Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of jasplakinolide (JSP), a stabilizer of F-actin, and latrunculin A (LTA), a destabilizer of F-actin, on a series of events occurring in the execution phase of staurosporine (STS)-induced apoptotic processes were studied using human osteosarcoma 143B cells. Time-dependent apparent increases of the population of cells with collapsed membrane potential of mitochondria (Delta Psi(m)) caused by STS treatment were not due to actual decreases in the Delta Psi(m) per cell, but due to the fragmentation of cells resulting in decreases in the number of active mitochondria per cell. Decreases in the Delta Psi(m) in fragmented cells occurred late in the execution phase. Both JSP and LAT failed to prevent STS-induced release of cytochrome c from mitochondria followed by the activation of caspases 3 and 9, the cleavage of poly (ADP-ribose) polymerase (PARP) and apoptotic nuclear fragmentation. However, both drugs prevented STS-induced apoptotic cell fragmentation and decreases in the Delta Psi(m). These results indicate that physicochemical states of actin filaments play a certain role in the execution phase of STS-induced apoptotic processes.
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PMID:Modification of physicochemical properties of actin filaments suppresses cell fragmentation in the execution phase of staurosporine-induced apoptotic processes. 1558 77

This study describes the molecular mechanism by which treatment with 3-AB, a potent inhibitor of PARP, allows human osteosarcoma MG-63 cells to restrict growth and enter differentiation. Our findings show that in MG-63 cells, aberrant gene expression keeps Rb protein constitutively inactivated through hyperphosphorylation and this promotes uncontrolled proliferation of the cells. After 3-AB-treatment, the poly(ADP-ribosyl)ation of nuclear proteins markedly decreases and this results in an increase in both the hypophosphorylated active form of Rb and pRb/E2F complexes. These effects are accompanied by G1 arrest, downregulation of gene products required for proliferation (cyclin D1, beta-catenin, c-Jun, c-Myc and Id2) and upregulation of those implicated in the osteoblastic differentiation (p21/Waf1, osteopontin, osteocalcin, type I collagen, N-cadherins and alkaline phosphatase). Our study suggests that use of PARP inhibitors may induce a remodeling of chromatin with the reprogramming of gene expression and the activation of differentiation.
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PMID:Differentiative pathway activated by 3-aminobenzamide, an inhibitor of PARP, in human osteosarcoma MG-63 cells. 1567 Aug 17

Syndecans are cell surface heparan sulfate proteoglycans that serve as co-receptors and modulate the actions of a number of extracellular ligands. Syndecans thereby regulate cell adhesion, proliferation, and differentiation. Studies in cancer cells suggest that syndecans may also modulate cell viability. We previously showed that syndecan-2 controls the growth of normal human osteoblastic cells. In this study, we examined the role of syndecan-2 in osteosarcoma cell proliferation and apoptosis. To this goal, MG63 osteosarcoma cells which express low syndecan-2 levels were transfected to overexpress full-length syndecan-2 or truncated syndecan-2 lacking its cytoplasmic domain. Determination of cell growth by cell counting and 3H-thymidine incorporation showed that truncated syndecan-2 inhibited MG63 cell proliferation. Flow cytometry analysis of DNA content and colony forming test revealed that syndecan-2, but not truncated syndecan-2, induced MG63 cell death. We show that characteristic features of apoptosis such as caspase activation, PARP cleavage, cytochrome c release, increased Bax expression, and DNA fragmentation were associated with syndecan-2-induced cell death. We further show that expression of full-length or truncated syndecan-2 induced differential activation of MAPK phosphorylation in MG63 cells. Notably, syndecan-2 but not truncated syndecan-2 overexpression increased JNK phosphorylation. Moreover, SP600125, a specific inhibitor of JNK, suppressed Bax expression induced by syndecan-2 overexpression, indicating that JNK activation mediates syndecan-2-induced apoptosis. The results show that syndecan-2 induces osteoblastic cell apoptosis through the JNK/Bax apoptotic pathway and that the cytoplasmic domain of syndecan-2 is required for this action. This supports a role for syndecan-2 in the regulation of osteosarcoma cell fate and identifies one signaling pathway by which syndecan-2 induces apoptosis in osteosarcoma cells.
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PMID:Syndecan-2 overexpression induces osteosarcoma cell apoptosis: Implication of syndecan-2 cytoplasmic domain and JNK signaling. 1593 98

Many studies have suggested that dietary flavonoids are anticancer agents that induce the apoptosis of cancer cells. However, the effects of flavonoids on the induction of apoptosis in osteosarcoma cells are unclear. Previously, a flavonoid fraction, consisting mainly of protocatechuic acid, fustin, fisetin, sulfuretin, and butein, herein named RCMF (the RVS chloroform-methanol fraction), was prepared from a crude acetone extract of Rhus verniciflua Stokes (RVS). This study evaluated the effects of RCMF on the proliferation and apoptosis using human osteosarcoma (HOS) cells. The mechanism of growth inhibition of the HOS cells by the flavonoid fraction, RCMF, was also assessed. The results demonstrated that RCMF exhibited sensitive growth inhibition and induced apoptosis in HOS cells. PARP cleavage was closely associated with the RCMF-induced apoptosis of the HOS cells. Furthermore, the activation of caspase 8 and Bax, the inhibition of Bcl-2 expression, and the release of cytochrome c are believed to be involved in the RCMF-mediated apoptosis. Collectively, these findings suggest that RCMF is an agent which may be capable of inducing sensitive growth inhibition and apoptosis in HOS cells.
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PMID:Flavonoids purified from Rhus verniciflua Stokes actively inhibit cell growth and induce apoptosis in human osteosarcoma cells. 1621 62

Previous studies have shown that oridonin, a diterpenoid isolated from Rabdosia rubescens, was able to inhibit proliferation and induce apoptosis in several cell types. But the mechanisms remain poorly understood. In this study, we investigated the apoptosis-inducing effect and mechanisms of action of oridonin in human osteosarcoma cells. Our results demonstrated that oridonin induced concentration- and time-dependent suppression of proliferation and activation of apoptosis in U2OS, MG63 and SaOS-2 osteosarcoma cell lines. Oridonin induced the release of cytochrome c accompanied by activation of caspase-9, caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). These events were all inhibited by z-VAD-fmk, a universal inhibitor of caspases. Oridonin treatment dephosphorylated constitutively active AKT, FOXO transcription factor, and glycogen synthase kinase 3 (GSK3). In addition, oridonin decreased the phosphorylation of ERK and increased the phosphorylation of p38 MAPK and JNK. Furthermore, oridonin treatment down-regulated the expression of the inhibitor of apoptosis protein(IAP) in osteosarcoma cells. All together, our results suggested that oridonin is able to inactivate Akt and ERK and activate p38 MAPK and JNK signalling pathways in osteosarcoma cells causing the suppression of proliferation and induction of mitochondria- and caspase-dependent apoptosis.
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PMID:Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells. 1721 75

Grifolin, a natural biologically active substance isolated from the edible bodies of the mushroom Albatrellus confluens, has been shown to inhibit proliferation and induce apoptosis in several cancer cell lines. But the mechanisms remain poorly understood. In this study, we investigated the apoptosis-inducing effects and the mechanisms of grifolin on human osteosarcoma cells. Our results demonstrated that grifolin induced concentration- and time-dependent suppression of proliferation and induction of apoptosis in U2OS and MG63 osteosarcoma cell lines. Grifolin induced the release of cytochrome c accompanied by activation of caspase-9, caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP). In addition, z-VAD-fmk, a universal inhibitor of caspases, prevented caspase-3 activation and PARP cleavage and inhibted grifolin-induced cell growth inhibition. Furthermore, grifolin treatment resulted in a reduction in level of phosphorylated AKT, FOXO transcription factor, and glycogen synthase kinase 3 (GSK3). Knockdown of GSK3 with siRNA inhibited the apoptotic effects of grifolin. On the other hand, grifolin treatment down-regulated the expression of the inhibitor of apoptosis protein(IAP) in both osteosarcoma cells. Taken together, our results suggested that grifolin is able to suppress the phosphorylation of Akt and its substrates FOXO transcription factor and GSK3 in osteosarcoma cells causing the suppression of proliferation and induction of mitochondria- and caspase-dependent apoptosis.
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PMID:Grifolin induces apoptosis via inhibition of PI3K/AKT signalling pathway in human osteosarcoma cells. 1733 16

Interferonalpha (IFNalpha) induces cell cycle arrest and triggers apoptosis and chemosensitivity. But the mechanism of IFNalpha in regulating chemosensitivity has not been fully understood. To study whether IFNalpha affected chemosensitivity of osteosarcoma cells, we treated p53-wild U2OS cells and p53-mutant MG63 cells with IFNalpha and etoposide, alone or in combination, and then examined growth inhibition, cell cycle arrest and apoptosis. IFNalpha enhanced etoposide-induced growth inhibition and apoptosis in p53-wild U2OS cells but not p53-mutant MG63 cells in a dose- and time-dependent manner. Etoposide-induced G2/M phase arrest was also enhanced by IFNalpha. The enhanced apoptosis was associated with the accumulation of transcriptionally active p53 accompanied with increased Bax and Mdm2, as well as decreased Bcl-2. IFNalpha also activated caspases-3, -8 and -9 protein kinases and PARP cleavage in response to etoposide in U2OS cells. Moreover, the combination-induced cytotoxicity and PARP cleavage were significantly reduced by caspase pan inhibitor and p53 siRNA. Thus we conclude that IFNalpha enhances etoposide-induced apoptosis in human osteosarcoma U2OS cells by a p53-dependent and caspase-activation pathway. The proper combination of IFNalpha and conventional chemotherapeutic agents may be a rational strategy for the treatment of human osteosarcoma with functional p53.
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PMID:Interferonalpha enhances etoposide-induced apoptosis in human osteosarcoma U2OS cells by a p53-dependent pathway. 1819 51

The growth inhibitory effect of a mixture of t,t conjugated linoleic acid isomers (t,t CLA) was investigated in the human osteosarcoma cell MG-63, with references to c9,t11 and t10,c12 CLA isomers. The t,t CLA effectively induced a cytotoxic effect in a time-dependent (0 to 6 d) and concentration-dependent (0 to 40 microM) manner, as compared to the reference and control treatments. The apoptosis and cell cycle related parameters were measured on the cells treated with 40 microM t,t CLA for 4 d. Flow cytometric analysis revealed that the t,t CLA treatment effectively increased the proportion of apoptotic cells with a low DNA content (sub G0/G1) and a marked loss of cells from the G0/G1 phase of the cell cycle, relative to other treatments. The occurrence of the characteristic morphological changes and DNA fragmentation confirmed the apoptosis. The level of Bax protein was increased, whereas the Bcl-2 expression was reduced. In addition, cytochrome c was released from the mitochondria into the cytosol, and the activation of caspase-3 led to the cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, the composition of linoleic and arachidonic acids in membrane was decreased by increase in t,t CLA. These findings suggest that t,t CLA incorporation in membrane activates a mitochondria-mediated apoptosis pathway that can enhance the antiproliferative effect of t,t CLA in the osteosarcoma cells.
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PMID:Growth inhibition of osteosarcoma cell MG-63 by a mixture of trans,trans conjugated linoleic acid isomers: possible mechanistic actions. 1821 79

In our previous studies, the bisindolic alkaloid voacamine (VOA), isolated from the plant Peschiera fuchsiaefolia, proved to exert a chemosensitizing effect on cultured multidrug resistant (MDR) osteosarcoma cells exposed to doxorubicin (DOX). In particular, VOA was capable of inhibiting P-glycoprotein action in a competitive way, thus explaining the enhancement of the cytotoxic effect induced by DOX on MDR cells. Afterwards, preliminary observations suggested that such an enhancement did not involve the apoptotic process but was due instead to the induction of autophagic cell death. The results of the present investigation demonstrate that the plant alkaloid VOA is an autophagy inducer able to exert apoptosis-independent cytotoxic effect on both wild-type and MDR tumor cells. In fact, under treatment condition causing about 50 percent of cell death, no evidence of apoptosis could be revealed by microscopical observations, Annexin V-FITC labeling and analysis of PARP cleavage, whereas the same cells underwent apoptosis when treated with apoptosis inducers, such as doxorubicin and staurosporine. Conversely, VOA-induced autophagy was clearly evidentiated by electron microscopy observations, monodansylcadaverine staining, LC3 expression, and conversion. These results were confirmed by the analysis of the modulating effects of the pretreatment with autophagy inhibitors prior to VOA administration. In addition, transfection of osteosarcoma cells with siRNA against ATG genes reduced VOA cytotoxicity. In conclusion, considering the very debated dual role of autophagy in cancer cells (protective or lethal, pro- or anti- apoptotic) our findings seem to demonstrate, at least in vitro, that a natural product able to induce autophagy can be effective against drug resistant tumors, either used alone or in association with conventional chemotherapeutics.
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PMID:The plant alkaloid voacamine induces apoptosis-independent autophagic cell death on both sensitive and multidrug resistant human osteosarcoma cells. 1883 62

The affinity of the poly(ADP-ribose) polymerase-1 (PARP-1) for platinum-damaged DNA was first discovered during photo-cross-linking experiments using the photoactive compound Pt-BP6 [J. Am. Chem. Soc.2004, 126, 6536-6537], an analogue of the anticancer drug cis-diamminedichloroplatinum(II), cisplatin. Although PARP inhibitors sensitize cancer cells to cisplatin, there are conflicting reports in the literature about their efficacy. In order to improve our understanding of the mechanism by which PARP inhibition might potentiate the cell-killing ability of cisplatin, and to shed light on the source of the discrepancy among different laboratories, we have in the present study probed the influence of three PARP inhibitors in four types of cancer cells, cervical (HeLa), testicular (NTera2), pancreatic (BxPC3), and osteosarcoma (U2OS), on the results of Pt-BP6 photo-cross-linking experiments and cytotoxicity assays. We find that the activity of PARP proteins following exposure to platinum-modified DNA results in the dissociation of DNA-bound proteins. PARP inhibitors were able to sensitize some, but not all, of the cell lines to cisplatin. This cell line-dependence and the potential consequences of PARP-initiated protein removal from platinum-DNA lesions are discussed. Control experiments revealed that NTera2 cells are especially sensitive to PARP inhibition.
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PMID:Poly(ADP-ribose) polymerase-1 activity facilitates the dissociation of nuclear proteins from platinum-modified DNA. 1897 44


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