Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to investigate the radioresistance mechanism of human carcinoma cells, we measured intracellular manganese- (Mn-) and copper/zinc- (Cu/Zn-) superoxide dismutases (SODs), glutathione (GSH) and poly (ADP-ribose) polymerase (PARP) in radioresistant N10 and its parental KB cell lines. The Mn-SOD level was 1.3-fold less in N10 than in KB, but Mn-SOD was induced at 1.3 to 1.5-fold higher level in N10 than in KB by X-irradiation (4 Gy). Cu/Zn-SOD in N10 showed a higher level than that in KB both without and with irradiation. In addition, N10 had a 1.65-fold higher GSH level than did KB and became radiosensitive on treatment with buthionine sulfoximine, an inhibitor of GSH. Furthermore, PARP mRNA was highly expressed in N10 as compared to KB under unirradiated conditions. X-Irradiation reduced the PARP mRNA level in KB in a time-dependent manner, whereas the PARP mRNA level in N10 was still high at 6 h postirradiation. Assay for PARP activity demonstrated an approximately 3-fold higher activity in N10 than in KB under unirradiated conditions. X-Irradiation caused a rapid induction of PARP activity within 1 h in both cell lines, but treatment of cells with nicotinamide, a PARP inhibitor, markedly reduced the enzyme induction in N10, but not in KB, and potentiated the radiosensitivity in N10. These factors may all contribute to the radioresistance of the N10 cell line.
Jpn J Cancer Res 1997 Nov
PMID:Levels of superoxide dismutases, glutathione, and poly(ADP-ribose) polymerase in radioresistant human KB carcinoma cell line. 943 82

We have demonstrated that ginsenoside Rh2 (G-Rh2), a ginseng saponin with a dammarane skeleton, induces apoptosis of human hepatoma SK-HEP-1 cells as evidenced by analyses of DNA fragmentation, flow cytometry and changes in cell morphology. Ac-YVAD-CMK or Ac-DEVD-CHO effectively prevented G-Rh2-induced DNA fragmentation, indicating the involvement of caspase-like proteases in the process of apoptosis. In addition, G-Rh2 induced the processing of caspase-3 to an active form, p17. In stable Bcl-2 transfectants, G-Rh2 also induced DNA fragmentation, while staurosporine-induced DNA fragmentation was totally blocked. As it did in wild-type cells, G-Rh2 induced the proteolytic activation of caspase-3 protease and subsequent cleavage of PARP in the bcl-2 transfectants. In summary, G-Rh2 contains an apoptotic inducing activity in SK-HEP-1 cells which functions via Bcl-2-insensitive activation of caspase-3, followed by proteolytic cleavage of PARP.
Cancer Lett 1997 Dec 16
PMID:Activation of caspase-3 protease via a Bcl-2-insensitive pathway during the process of ginsenoside Rh2-induced apoptosis. 945 77

Apoptosis induced by numerous cancer chemotherapeutic and other toxic agents has been shown to proceed through a cascade of proteases, now termed caspases, culminating in cleavage of a set of proteins. The ability of photodynamic treatment (PDT) with the phthalocyanine Pc 4 to activate cellular caspases has been assessed during the rapid apoptosis in murine lymphoma L5178Y-R cells. Cells were exposed to combinations of Pc 4 and activating red light that result in > or =90% cell death, as judged by a clonogenic assay. The rate of entry of cells into apoptosis was dose dependent. For 0.5 microM Pc 4 and either 2.1 or 3 kJ/m2, which kill 90 or 99.9% of the cells, oligonucleosomal fragmentation was visible on agarose gels as early as 60 or 30 min after PDT, respectively. To assess caspase activation, cells were harvested at various times after PDT, and cell proteins were subjected to electrophoresis and Western blot analysis, using an antibody to poly(ADP-ribose) polymerase (PARP). The cleavage of the normally Mr 116,000 PARP into fragments of Mr approximately 90,000 was observed at approximately the same time as the earliest DNA fragmentation. An antibody to the polymer, poly(ADP-ribose), did not recognize the Mr approximately 90,000 PARP cleavage products, in contrast to the parent enzyme. This analysis also revealed that levels of a poly(ADP-ribosylated) Mr 100,000 protein, tentatively identified as topoisomerase I, were maintained in cells after PARP was fully cleaved. Caspase-3 (and/or caspase-7) activity, as measured in cell lysates with the fluorogenic substrate DEVD-AMC, was elevated almost immediately after PDT. The cell-permeable, irreversible caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp(O-methyl)-fluoro-methylketone, inhibited PDT-induced apoptosis and PARP cleavage, whereas the inactive peptide analogue, benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone, was without effect. The results indicate that PDT-induced apoptosis is mediated by activation of caspase-3 and/or other similar caspases.
Cancer Res 1998 Mar 01
PMID:Protease activation and cleavage of poly(ADP-ribose) polymerase: an integral part of apoptosis in response to photodynamic treatment. 950 Apr 54

Inhibitors of poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) are of clinical interest because they have potential for improving radiation therapy and chemotherapy of cancer. The refined binding structures of four such inhibitors are reported together with the refined structure of the unligated catalytic fragment of the enzyme. Following their design, all inhibitors bind at the position of the nicotinamide moiety of the substrate NAD+. The observed binding mode suggests inhibitor improvements that avoid other NAD(+)-binding enzymes. Because the binding pocket of NAD+ has been strongly conserved during evolution, the homology with ADP-ribosylating bacterial toxins could be used to extend the bound nicotinamide, which is marked by the inhibitors, to the full NAD+ molecule.
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PMID:Inhibitor and NAD+ binding to poly(ADP-ribose) polymerase as derived from crystal structures and homology modeling. 952 10

Signal transduction pathways involving the c-Raf protein kinase are frequently activated in tumor cells. We have addressed the relevance of this activation by a loss-of-function approach. An anti-sense phosphorothioate oligonucleotide (ODN) specifically targeted against c-raf mRNA (Monia et al., 1996a) was used to block c-Raf protein expression in four different cell lines derived from lung, cervical, prostate and colon carcinomas. Concomitant with the abrogation of c-Raf expression we observed the occurrence of classical apoptotic markers, including chromatin condensation, inter-nucleosomal DNA cleavage, annexin V binding and cleavage of PARP, which was followed by cell death, affecting most of the cell population. This induction of apoptosis occurred independent of the p53 status of the cell. These findings demonstrate that c-Raf can protect tumor cells from undergoing programmed cell death, and suggest that the interference with c-Raf expression or function by ODNs or specific drugs could represent a powerful means for improving the efficacy of anti-cancer therapy.
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PMID:Abrogation of c-Raf expression induces apoptosis in tumor cells. 958 88

Poly(ADP-ribose)polymerase (PARP) has been implicated in DNA repair mechanisms and the associated activity shown to markedly increase after DNA damage in carcinogen-treated cells. A defective DNA repair has been associated to the aetiology of human cancers. In order to assess the potential role of this enzyme in cellular response to DNA damage by gamma-radiation, we studied the activity of PARP in patients with familial adenomatous polyposis (FAP). We compared poly(ADP-ribose)polymerase activity by the rate of incorporation of radioactivity from [3H]adenine-NAD+ into acid-insoluble material in permeabilized leucocytes from FAP patients and healthy volunteers. Concomitantly, the intracellular levels of NAD+--the substrate for the PARP--and the reduced counterpart NADH were determined using an enzymatic cycling assay 30 min after [60Co] gamma-ray cells irradiation. Our results demonstrate that a marked stimulation of PARP activity is produced upon radiation of the cells from healthy subjects but not in the FAP leucocytes, which concomitantly show a marked decrease in total NAD-/NADH content. Our observations point to a role of PARP in the repair of the gamma-radiation-induced DNA lesions through a mechanism that is impaired in the cells from FAP patients genetically predisposed to colon cancer. The differences observed in PARP activation by gamma-radiation in patients and healthy individuals could reflect the importance of PARP activity dependent on treatment with gamma-rays. The absence of this response in FAP patients would seem to suggest a possible defect in the role of PARP in radiation-induced DNA repair in this cancer-prone disease.
Br J Cancer 1998 May
PMID:Absence of stimulation of poly(ADP-ribose) polymerase activity in patients predisposed to colon cancer. 963 38

The anti-tumor drug Flavopiridol is a potent inhibitor of cyclin-dependent kinases (cdks). As a consequence, Flavopiridol-treated cells arrest in both G1 and G2, but Flavopiridol has also been shown to be cytotoxic for some tumor cell lines. The underlying molecular events are, however, unclear. We now show that Flavopiridol induces apoptosis in human umbilical vein endothelial cells (HUVECs), as judged by the occurrence of classical apoptotic markers, including chromatin condensation, internucleosomal cleavage, DNA fragmentation (TUNEL assay), annexin V binding and poly(ADP-ribose) polymerase (PARP)-cleavage. Such induction of apoptosis occurs with equal efficiency in both proliferating and G0/G1-arrested cells. Because growth-arrested HUVECs lack cdk2 activity and contain high levels of the cdk inhibitor p27, our observations suggest that cell cycle regulated cdks may not be the only critical target for Flavopiridol-induced apoptosis. Surprisingly, A549 lung carcinoma cells were clearly dependent on cell proliferation for the induction of cell death, pointing to cell type-related differences in the mechanism of Flavopiridol action.
Int J Cancer 1998 Jul 03
PMID:Cell cycle-independent induction of apoptosis by the anti-tumor drug Flavopiridol in endothelial cells. 963 6

Four volunteers were involved for 5 weeks of a baseline period, followed by 7 weeks of a combined supplementation of nicotinamide, zinc, and carotenoids (Nicoplex). Blood sampling and bioassays were carried out every week during the evaluation period. The supplementation of Nicoplex resulted in statistically significant increased resistance to DNA single-strand breaks induced by H2O2 (DNA retained on filter % from 46.7 +/- 1.9 to 59.4 +/- 4.3; p < 0.01), increased DNA repair 60 min after induction of damage (DNA retained on filter % from 74.6 +/- 4.8 to 88.3 +/- 4.2; p < 0.01), elevated poly (ADP-ribose) polymerase (PARP) activity (p < 0.05), and an increased proliferative response to phytohemagglutinin (PHA) (p < 0.05) when compared with the levels before supplementation. However, when the same subjects were supplemented with nicotinamide, zinc, and carotenoids together with another 17 nutrients or minerals, there were no changes in DNA damage, DNA repair, or proliferative response to PHA. Through the use of a rat model, DNA repair of splenocytes 3 h after 12 Gy whole-body irradiation was significantly enhanced in rats supplemented with Nicoplex for 6 weeks (p < 0.05) and 8 weeks (p < 0.01). Comparison of Nicoplex and its components administered separately revealed that there was an additive effect on DNA repair for both single- and double-strand breaks (both p < 0.05). On the basis of the results, it is hypothesized that the enhanced effect of combined supplement of nicotinamide, zinc, and carotenoids on DNA repair depends on their diversified mechanisms of action while multinutrient supplementation may compromise the effects by inhibitory interactions including uptake and absorption.
Cancer Detect Prev 1998
PMID:DNA repair enhancement by a combined supplement of carotenoids, nicotinamide, and zinc. 967 71

Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity.
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PMID:Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. 968 Mar 69

Inhibitors of poly(ADP-ribose)polymerase (PARP) inhibit repair of damaged DNA and thus potentiate radiotherapy and chemotherapy of cancer. 3-Substituted benzamides and 5-substituted isoquinolin-1-ones have been synthesised and evaluated for inhibition of PARP. Reduction of 3-(bromoacetyl)benzamide, followed by treatment with base, gave RS-3-oxiranylbenzamide. Reduction of 3-(hydroxyacetyl)benzonitrile with bakers' yeast gave the R-diol which was converted to R-3-(1,2-dihydroxyethyl)benzamide. Similar reduction of 3-(acetoxyacetyl)benzonitrile led towards the S-diol which was converted to its cyclic acetonide. E-2-(2,6-Dicyanophenyl)-N,N-dimethylethenamine was formed by condensation of 2,6-dicyanotoluene with dimethylformamide dimethyl acetal (DMFDMA); cyclisation under acidic conditions afforded 5-cyanoisoquinolin-1-one. Heck coupling of 5-iodoisoquinolin-1-one with propenoic acid formed E-3-(1-oxoisoquinolin-5-yl)propenoic acid. 3-Oxiranylbenzamide, 5-bromoisoquinolin-1-one and 5-iodoisoquinolin-1-one were among the most potent inhibitors of PARP activity in a preliminary screen in vitro.
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PMID:Synthesis of 3-substituted benzamides and 5-substituted isoquinolin-1(2H)-ones and preliminary evaluation as inhibitors of poly(ADP-ribose)polymerase (PARP). 968 Nov 38


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