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)

Apoptosis is not only essential for homeostasis in normal cells but also in cancer cells, in which it is associated with cell death mechanisms caused by novel therapeutics. We have previously reported that interleukin-13 receptors (IL-13R) are constitutively overexpressed on a majority of human malignant glioma cell lines and primary cell cultures. In addition, we have reported that IL-13 cytotoxin, comprised of human IL-13 and a mutated form of Pseudomonas exotoxin, is highly and specifically cytotoxic to these cells and can lead to pronounced antitumor activity in malignant glioma tumors in animal models. However, the molecular mechanisms of tumor cytotoxicity induced by IL-13 cytotoxin are poorly understood. In this study, we demonstrate that glioma tumors undergo apoptotic cell death on intratumoral administration of IL-13 cytotoxin. This conclusion was made based on (a) time-dependent induction of several proapoptotic molecules, such as caspases (caspase-3, -8, and -9) in tumors; (b) cleavage of procaspase-3 and poly(ADP-ribose) polymerase (PARP); and (c) the release of cytochrome c from mitochondria to the cytosol on injection of IL-13 cytotoxin in U251 glioblastoma tumors established in immunodeficient animals. These indicators of two major pathways of apoptosis were detected in tumors even though IL-13 cytotoxin was no longer present in tumors. In addition, we found that inducible nitric oxide was expressed in tumors in a time-dependent manner with primary localization in infiltrating phagocytes after treatment with IL-13 cytotoxin. These studies demonstrate that IL-13 cytotoxin mediates apoptotic death of glioma cells, resulting in regression of established tumors. Our studies will help unravel the molecular pathways of cell death associated with tumor regression and provide additional insight and define apoptosis as possible surrogate marker of tumor response.
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PMID:Intratumor administration of interleukin 13 receptor-targeted cytotoxin induces apoptotic cell death in human malignant glioma tumor xenografts. 1248 22

Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear zinc finger DNA-binding protein that is implicated in the repair of DNA damage. Inhibition of PARP-1 through genetic knockouts causes cells to become hypersensitive to various chemotherapeutic agents. We tested the chemopotentiating ability of the PARP-1 inhibitor, CEP-6800, when used in combination with temozolomide (TMZ), irinotecan (camptothecin or SN38), and cisplatin against U251MG glioblastoma, HT29 colon carcinoma, and Calu-6 non-small cell lung carcinoma xenografts and cell lines, respectively. Exposure of tumor cells to TMZ, camptothecin (or SN38), and cisplatin before, or in the presence of, CEP-6800 significantly increased the onset and the magnitude of DNA damage, the duration for cells to effect repair, and the onset, duration, or fraction of cells arrested at the G(2)/M boundary. In addition, in vivo biochemical efficacy studies with CEP-6800 showed that it was able to attenuate irinotecan- and TMZ-induced poly(ADP-ribose) accumulation in LoVo and HT29 xenografts, respectively. Treatment of CEP 6800 (30 mg/kg) with TMZ (17 and 34 mg/kg) resulted in 100% complete regression of U251MG tumors by day 28 versus 60% complete regression caused by TMZ alone. CEP-6800 (30 mg/kg) in combination with irinotecan (10 mg/kg) resulted in a 60% inhibition of HT29 tumor growth versus irinotecan alone by day 33. The combination therapy of cisplatin (5 mg/kg) with CEP-6800 (30 mg/kg) caused a 35% reduction in Calu-6 tumor growth versus cisplatin alone by day 28. These data suggest that CEP-6800 could be used as a chemopotentiating agent with a variety of clinically effective chemotherapeutic agents.
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PMID:Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. 1270 Feb 81

Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been used to treat human cancers in China since 1984. It was recently found to be capable of inducing apoptosis in human colon carcinoma, hepatoma and glioblastoma cells by way of an elusive mechanism. In this study, we demonstrated that NCTD also induces apoptosis in human oral cancer cell lines SAS (p53 wild-type phenotype) and Ca9-22 (p53 mutant) as evidenced by nuclear condensation, TUNEL labeling, DNA fragmentation and cleavage of PARP. Apoptosis induced by NCTD was both dose- and time-dependent. We found NCTD did not induce Fas and FasL, implying that it activated other apoptosis pathways. Our data showed that NCTD caused accumulation of cytosolic cytochrome c and activation of caspase-9, suggesting that apoptosis occurred via the mitochondria mediated pathway. NCTD enhanced the expression of Bax in SAS cells consistent with their p53 status. Moreover, we showed that NCTD downregulated the expression of Bcl-2 in Ca9-22 and Bcl-XL in SAS. Our results suggest that NCTD-induced apoptosis in oral cancer cells may be mediated by an increase in the ratios of proapoptotic to antiapoptotic proteins. Since oral cancer cells with mutant p53 or elevated Bcl-XL levels showed resistance to multiple chemotherapeutic agents, NCTD may overcome the chemoresistance of these cells and provide potential new avenues for treatment.
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PMID:Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. 1559 95

Necrosis in glioblastoma is often associated with high levels of Fas (APO-1), HIF-1alpha and PARP expression. The presence of such molecules suggests a regulative element to cell death within this tissue, which may involve p53. We aimed to establish whether p53 and its downstream targets Bax, MDM2 and p21 play a role in perinecrotic cell death in glioblastoma. Following sequencing of the p53 gene in U87 and U373 glioma cell lines, p53 was found to be reactive in the p53 wild-type line U87 in response to hypoxia but not in the p53 mutant line, U373. Although no increase in perinecrotic p53 expression was detected in spheroid cultures derived from these lines, a 60 kDa MDM2 isoform lacking a C-terminal domain showed perinecrotic localization, irrespective of p53 status. Similar findings were observed surrounding regions of necrosis in 80% of glioblastoma biopsies examined. Increasing levels of wild-type p53 did not affect cell death in U87 spheroid cultures but killed all U373 cells 3 days post transfection. Dominant negative p53 did not affect cell death in U373 and U87 spheroid cultures. Although p53 accumulation appeared not to be important for the onset of cell death both in spheroid and biopsy cases, high levels of perinecrotic 60 kDa MDM2 may have implications for glioma cell death susceptibility in both p53 mutant and wild-type tumour cell populations.
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PMID:Discovery of a perinecrotic 60 kDa MDM2 isoform within glioma spheroids and glioblastoma biopsy material. 1577 12

The nuclear receptors PPARs (peroxisome proliferator-activated receptors) are transcription factors activated by specific ligands. PPARs play an important role in carcinogenesis, inflammation, atherosclerosis, lipid metabolism and diabetes. There is evidence that activation of PPARs by specific ligands is able to suppress the growth of different types of human cancer by mechanisms including the growth arrest, apoptosis and induction of differentiation, although the detailed signalling pathways have not been completely elucidated to date. The aim of our study was to determine whether synthetic ligands of PPARalpha and PPARgamma could affect the viability, proliferation, differentiation, apoptosis and expression of some cell cycle related proteins in glial tumor cell lines. The study was performed on human glioblastoma cell lines U-87 MG, T98G, A172 and U-118 MG. Cell lines were treated by ligands of PPARalpha (bezafibrate, gemfibrozil) and PPARgamma (ciglitazone). MTT, flow cytometry, TUNEL assay and immunoblotting were used for detection of changes in cell viability, proliferation, differentiation and apoptosis. Bezafibrate, ciglitazone and gemfibrozil inhibited viability of glioblastoma cell lines. The synthetic ligands significantly reduced or induced the expression of cyclins, p27Kip1, p21Waf1/Cip1, MDM-2, Bcl-2, Bax, PARP, Caspase 3, androgen receptors, etc. and did not affect the expression of the differentiation marker GFAP. Flow cytometry confirmed arrest of the cell cycle although the detection of apoptosis was controversial. Apart from hypolipidemic and hypoglycaemic effects, PPAR ligands may also have significant cytostatic effects of potential use in anticancer treatment.
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PMID:Peroxisome proliferator-activated receptors (PPAR) agonists affect cell viability, apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors. 1580 Jul 11

Primary glioblastomas (GBMs) commonly overexpress the oncogene epidermal growth factor receptor (EGFR), which leads to increased Ras activity. FTA, a novel Ras inhibitor, produced both time- and dose-dependent caspase-mediated apoptosis in GBM cell lines. EGFR-mediated increase in 3H-thymidine uptake was inhibited by FTA. FACS analysis was performed to determine the percent of apoptotic cells. The sub-Go population of GBM cells was increased from 4.5 to 13.8% (control) to over 45-53.6% in FTA-treated cells within 24 h. Furthermore, FTA also increased the activities of both caspase-3 and -9, and PARP cleavage. Treatment of GBMs with FTA before or after EGF addition to the cultures blocked phosphorylation of Akt and mitogen-activated protein kinases (MAPK). FTA also significantly reduced the amount of EGF-induced Ras-GTP as reflected by a decrease in the level of Ras bound to Raf-RBD-GST. This study demonstrates that inhibition of Ras methylation may provide a therapeutic target for the treatment of GBMs overexpressing EGFR.
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PMID:Farnesylthiosalicylic acid induces caspase activation and apoptosis in glioblastoma cells. 1623 32

Smac/DIABLO is a mitochondrial protein released into cytosol during the progression of apoptosis. Smac/DIABLO promotes apoptosis by neutralizing the inhibitory effect of the inhibitor of apoptosis proteins (IAPs) on the processing and activity of the effecter of caspase. Here, we generated synthetic Smac peptide which possesses an IAP-binding domain and Drosophila antennapaedia penetration sequence, and examined whether it enhances the effect of the chemotherapeutic agent etoposide in the human glioblastoma cell line. Cellular uptake of Smac peptide in several glioma cell lines was most prominent at 6-12 h after addition. Caspase activity assay showed that our peptide successfully increased the activity of caspase-3 and caspase-9 in etoposide-induced apoptosis. In addition, Smac peptide increased the amount of cleaved PARP (poly ADP-ribose polymerase), but control peptides did not. Moreover, the addition of z-VAD-fmk, a caspase inhibitor, counterbalanced the effect of Smac peptide. Finally, we demonstrated that Smac peptide could enhance the growth inhibition effect of etoposide compared with control peptides. These results suggest that synthetic Smac peptide may be a new molecular targeting anti-tumor therapy for human glioblastoma.
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PMID:Synthetic Smac peptide enhances the effect of etoposide-induced apoptosis in human glioblastoma cell lines. 1657 41

Lithium is the most widely prescribed mood stabilizer, but the precise molecular mechanisms underlying its therapeutic function are not yet fully elucidated. Recent preclinical and clinical evidence indicates its neuroprotective and neurotrophic effects. As a tight coupling of function and metabolism in the central nervous system between glial cells and neurons has recently been detected, lithium's effect on glial cells may participate also in the total beneficial effects of this drug. The aim of the present study was to analyze molecular mechanisms induced in human glioblastoma A1235 cells by the treatment with lithium, especially its influence on the expression of apoptosis-related genes. Lower levels of lithium (0.5 mmol/L and 2 mmol/L) did not cause any cytotoxicity or changes in the cell cycle phase distribution following 72 h incubation. However, a higher dose (20 mmol/L) was cytostatic for glioblastoma cells, and caused accumulation of cells in G(2)/M phase of the cell cycle. The treatment with lithium did not alter the levels of Bcl-2 or procaspase-3 and did not cleave PARP, but increased the levels of p21(WAF/Cip1) and survivin. Thus, increased expression of p21(WAF/Cip1) (a protein with antiapoptotic function), and survivin (a protein that supports the growth of cells by suppression of apoptosis and promotion of cell proliferation) may be the early events in the long-term cell response to lithium that are involved in the beneficial effects of this drug.
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PMID:Lithium increases expression of p21(WAF/Cip1) and survivin in human glioblastoma cells. 1710 31

Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to DNA topoisomerase I (TOPO I) inhibitor-mediated apoptosis. We investigated the effects of combined treatments with the DNA topoisomerase I inhibitor Topotecan and the poly(ADPR)polymerase-1 inhibitor NU1025 in D54(p53wt) and U251(p53mut) glioblastoma cell lines. Analysis of cell growth and cell cycle kinetics showed a synergistic anti-proliferative effect of 10 nM TPT and 10 microM NU1025 and a G2/M block of the cell cycle. We also evaluated, the influence of TPT+/-NU1025 treatment on PARP-1 and p53 activity. We got evidences of a TPT-dependent increase of PARP-1 auto-modification level in both the cells. Moreover, in the D54(p53wt) cells we found that in co-treatments NU1025 incremented the TPT-dependent stimulation of p53 transcriptional activity and increased the p21 nuclear amount. Conversely, in U251(p53mut) cells we found that NU1025 incremented the TPT-dependent apoptosis characterised by PARP-1 proteolysis. Our findings suggest that the modulation of PARP-1 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status.
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PMID:Poly(ADPR)polymerase-1 signalling of the DNA damage induced by DNA topoisomerase I poison in D54(p53wt) and U251(p53mut) glioblastoma cell lines. 1712 74

High-grade gliomas comprise the most malignant type of primary brain tumor and are relatively frequent in adults. Recent studies have indicated that the loss of p16, an inhibitor of CDK4, promotes the acquisition of malignant characteristics in gliomas. A correlation between overexpression of urokinase-type plasminogen activator receptor (uPAR) and glioblastoma invasion has also been established. Moreover, uPAR/integrin binding has been shown to initiate or potentiate integrin signaling through focal adhesion kinase and/or src kinases. Our previous studies demonstrated that downregulation of uPAR expression and restoration of p16 regress glioma growth in nude mice and downregulate alphavbeta3 integrin receptor expression. Here, we show the effect of a bicistronic construct on alphavbeta5 integrin receptor expression, angiogenesis and the biochemical pathway that causes glioma cell death. The U251 glioblastoma and a glioblastoma xenograft cell line transduced with a recombinant replication-defective adenovirus vector containing the cDNA of wild-type p16 and antisense RNA of uPAR significantly inhibited human mammary epithelial cell capillary formation and vascular endothelial growth factor (VEGF) expression. Inactivation of anti-apoptotic molecules such as Akt, PARP, activation of caspases and accumulation of heteroduplex chromosomal DNA in pre-G1 phase of the cell cycle was demonstrated by Western blotting, caspase activity assay and FACS analysis. Nuclear DNA fragmentation upon induction of apoptosis was scored using the TUNEL assay. Significant downregulation of alphavbeta5 integrin receptor expression was also confirmed by FACS analysis, immunoprecipitation and RT-PCR. Taken together, the results demonstrate that the sense p16 and anti-sense uPAR bicistronic construct significantly inhibits angiogenesis, induces apoptosis by deregulation of the PI3K-Akt pathway and downregulates alphavbeta5 integrin receptor expression.
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PMID:Sense p16 and antisense uPAR bicistronic construct inhibits angiogenesis and induces glioma cell death. 1727 68


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