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)

Poly(ADP-ribose) polymerase (PARP) is well known for its involvement in DNA repair, although the underlying mechanisms remain unclear. Poly(ADP-ribose) is synthesized on nuclear proteins in response to DNA damage and consequently implicated in the toxicity of various xenobiotics, including anticancer agents. The metabolism of poly(ADP-ribose) in cisplatin (DDP)-sensitive (O342) and -resistant (O-342/DDP) rat ovarian tumor cells was investigated to explore its possible roles in DDP resistance. The poly(ADP-ribose) synthesis assayed as [3H]-NAD incorporation was higher by up to two-fold in the resistant O-342/DDP cells, when compared with that of its DDP-sensitive subline O-342. Furthermore, this difference still existed even in the presence of saturating concentrations of a double-stranded octameric deoxynucleotide that stimulates the enzyme directly, indicating a higher maximal poly(ADP-ribosyl)ation capacity of the resistant cells. In addition, acute treatment of O-342 cells with DDP also stimulated the polymer synthesis by up to 1.6-fold, which was totally suppressed by inclusion of 2.5 mM 3AB in the post-exposure incubation. Western blot analysis, however, failed to reveal higher levels of the enzyme proteins in the resistant cells. A higher level of endogenous DNA single strand breaks was also detected in both intact and permeabilized cells of O-342/DDP line. Taken together, these results demonstrate that the DDP resistance phenotype in these rat ovarian tumor cells is accompanied by a higher cellular poly(ADP-ribosyl)ation capacity, which may be linked with DDP resistance by enhancing the repair of DDP-inflicted DNA damage.
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PMID:Increased poly(ADP-ribose) formation in cisplatin-resistant rat ovarian tumor cells. 797 72

At a concentration of 2.5 mM, nicotinamide (NA), an inhibitor of poly(ADP-ribose) polymerase (PARP), significantly potentiated the cytotoxicity of cisplatin (DDP) in a DDP-resistant rat ovarian tumor cell line (O-342/DDP) in vitro, whereas the same treatment had no substantial effect on DDP's cytotoxic activity against the DDP-sensitive parental line (O-342). Furthermore, in a nude mouse model where the O-342/DDP tumor grew intraperitoneally, whereas DDP given alone at 1 mg/kg x 3 exhibited no antitumor activity as compared with control values due to the resistance, NA given at a nontoxic dose (5 mmol/kg x3) significantly increased the mean survival time (MST) of the tumor-bearing NMRI nude mice from 20.7 days in the DDP-treated group to 29.0 days in the combination group. Mechanism studies showed that endogenous PARP activity (incorporation of tritiated nicotinamide adenine dinucleotide, [3H]-NAD) was 2.6 times higher in O-342/DDP than in O-342 cells and that the presence of 2.5 mM NA during the incubation with the isotope resulted in 73.3% inhibition of the enzyme activity in O-342/DDP cells but in only about 30% inhibition in the sensitive line. However, treatment with NA during and after DDP exposure failed to produce any significant effect on the formation of DNA single-strand breaks (SSB) but decreased the induction of DNA interstrand cross-links (ISCL) by DDP in the sensitive and resistant cell lines. These results suggest that NA might have some clinical potential in reversing DDP resistance, and further studies are therefore warranted to confirm the resistance-reversing effect of NA in other DDP-resistant cell lines.
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PMID:Reversal of acquired cisplatin resistance by nicotinamide in vitro and in vivo. 826 76

Poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30) is a nuclear enzyme possibly involved in DNA base excision repair. The presence of single- or double-strand breaks in DNA stimulates this enzyme to covalently modify acceptor proteins with poly(ADP-ribose) in a reaction that uses NAD+ as substrate. To test the hypothesis that increased PARP activity could promote resistance towards DNA-damaging agents and gamma-radiation, we established stable rat cell transfectants that constitutively express human PARP. A number of subclones that showed different levels of PARP activity were isolated from two primary transfectants of different clonal origin. PARP activity was determined in permeabilized cells after maximal stimulation with a short, double-stranded oligonucleotide. Activity in different human PARP-expressing subclones was increased 1.6- to 3.1-fold compared with non-expressing subclones. In vivo labeling of poly(ADP-ribose) was performed in one of these subclones, revealing that the level of poly(ADP-ribose) accumulation after the same treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was four times higher in the human PARP-expressing subclone compared with both non-expressing transfected control cells and parental cells. Clonal survival assays revealed a sensitization upon treatment with gamma-radiation (up to 1.4-fold) or MNNG (up to 2.7-fold) of several subclones expressing human PARP; in some others survival was not changed. Survival after cisplatin (DDP) treatment remained essentially unchanged. A protective effect against DNA-damage was never observed. We conclude that human PARP overexpression in rodent cells leads to increased poly(ADP-ribosyl)ation capacity and does not promote survival after gamma-radiation or treatment with the DNA-damaging agents MNNG or DDP.
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PMID:Functional overexpression of human poly(ADP-ribose) polymerase in transfected rat tumor cells. 911 Nov 97

The purine analogue 2-chlorodeoxyadenosine (CdA) is unique compared with traditional antimetabolite drugs, as it has shown equal activity in dividing and resting lymphocytes. Poly(ADP-ribose)polymerase (PARP) activation and consecutive NAD+ consumption have been associated with the induction of apoptosis in resting cells. The potential of CdA to induce the p53-dependent DNA damage response was assessed in resting and phytohaemagglutinine (PHA)-activated peripheral blood mononuclear cells (PBMCs) and compared with cisplatin (DDP), a cell cycle-dependent and DNA-damaging agent that is mainly used in the treatment of solid tumours. Both drugs induced transactivation of the p53 target genes waf1 and mdm2, NAD+ consumption and apoptotic death. The expression pattern of p53 and waf1 suggests a partly p53-independent induction of waf1. The expression of c-myc and PARP, which both have a dual role in proliferation and apoptosis, was selectively induced by CdA. Cell cycle stimulation increased the cytotoxic activity of both drugs. These data show that DDP is also a potent inducer of apoptosis in resting and proliferating peripheral blood mononuclear cells. Activation of the p53-dependent DNA damage response seems to be an important component of the toxic effect of CdA.
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PMID:Similarity of apoptosis induction by 2-chlorodeoxyadenosine and cisplatin in human mononuclear blood cells. 940 Sep 41

Breast cancer has a prodigious capacity to metastasize to bone. In women with advanced breast cancer and bone metastases, bisphosphonates reduce the incidence of hypercalcaemia and skeletal morbidity. Recent clinical findings suggest that some bisphosphonates reduce the tumour burden in bone with a consequent increase in survival, raising the possibility that bisphosphonates may have a direct effect on breast cancer cells. We have investigated the in vitro effects of bisphosphonates zoledronate, pamidronate, clodronate and EB 1053 on growth, viability and induction of apoptosis in three human breast cancer cell lines (MDA-MB-231, Hs 578T and MCF-7). Cell growth was monitored by crystal violet dye assay, and cell viability was quantitated by MTS dye reduction. Induction of apoptosis was determined by identification of morphological features of apoptosis using time-lapse videomicroscopy, identifying morphological changes in nucleis using Hoechst staining, quantitation of DNA fragmentation, level of expression of bcl-2 and bax proteins and identification of the proteolytic cleavage of Poly (ADP)-ribose polymerase (PARP). All four bisphosphonates significantly reduced cell viability in all three cell lines. Zoledronate was the most potent bisphosphonate with IC50 values of 15, 20 and 3 microM respectively in MDA-MB-231, MCF-7 and Hs 578T cells. Corresponding values for pamidronate were 40, 35 and 25 microM, whereas clodronate and EB 1053 were more than two orders of magnitude less potent. An increase in the proportion of cells having morphological features characteristic of apoptosis, characteristic apoptotic changes in the nucleus, time-dependent increase in the percentage of fragmented chromosomal DNA, down-regulation in bcl-2 protein and proteolytic cleavage of PARP, all indicate that bisphosphonates have direct anti-tumour effects on human breast cancer cells.
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PMID:Bisphosphonates induce apoptosis in human breast cancer cell lines. 1078 May 27

The insulin-like growth factor (IGF) system and type-I IGF receptor (IGF-IR) signaling are involved in protecting against chemotherapeutic drug-induced cell death in human hepatoma cells. Acetaminophen (AAP) hepatotoxicity is the leading cause of liver failure, and the prevention of AAP-induced cell death has been the focus of many studies. We determined whether IGF-I could protect against AAP-induced cell death in Chang liver cells and investigated the protective mechanism. Based on the results of MTS assays, LDH release assays, Hoechst 33342 cell staining, and DNA fragmentation experiments, AAP induced cell death in a dose-dependent manner. According to Western blot analysis, treatment with AAP increased the level of poly(ADP-ribose) polymerase (PARP) fragments in cells compared with that in control cells; however, caspase-3, a critical signaling molecule in apoptosis, was not activated after AAP overdose. Moreover, combined treatment with AAP and IGF-I inhibited PARP cleavage, which was consistent with the ability of IGF-I to restore the level of glutathione (GSH) and cell viability in GSH and MTS assays, respectively. We investigated whether the protective effect of IGF-I against AAP cytotoxicity is related to the extracellular signal-related kinase ERK1/2, which is generally activated by mitogenic and proliferative stimuli such as growth factors. Compared with AAP treatment alone, IGF-I and AAP co-treatment increased ERK1/2 phosphorylation but inhibited PARP cleavage. Thus ERK1/2 activation is instrumental in the protective effect of IGF-I against AAP-induced cell death in Chang liver cells.
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PMID:Chemoprotective effect of insulin-like growth factor I against acetaminophen-induced cell death in Chang liver cells via ERK1/2 activation. 1716 76

[[trans-PtCl(NH(3))(2)](2)mu-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)-NH(2))(2))](4+) (BBR3464) is a cationic trinuclear platinum drug that is being evaluated in phase II clinical trials for treatment of lung and ovarian cancers. The structure and DNA binding profile of BBR3464 is different from drugs commonly used clinically. It is of great interest to evaluate the difference between the mechanisms of uptake employed by BBR3464 and cisplatin (c-DDP), as altered uptake may explain chemoresistance. Using transfected cell lines, we show that both c-DDP and BBR3464 use the copper transporter hCTR1 to enter cells and to a lesser extent, the ATP7B transporter to exit cells. Copper influenced c-DDP and BBR3464 uptake similarly; it increased the c-DDP and BBR3464 uptake in ovarian (A2780) and colorectal (HCT116) carcinoma cell lines as detected by ICP-OES. However, the effects of copper on c-DDP- and BBR3464-mediated cytotoxicity differed. Copper decreased c-DDP-induced apoptosis, caspase-3/7 activation, p53 induction and PARP cleavage in cancer cell lines. In contrast, copper increased BBR3464-induced apoptosis, and had little effect on caspase activation, PARP cleavage, and p53 induction. It was concluded that BBR3464 employs mechanisms of intracellular action distinct from c-DDP. Although these drugs use the same cellular transporters (hCTR1 and ATP7B) for influx and efflux, downstream effects are different for the two drugs. These experiments illustrate fundamental differences in the mechanisms of action between cisplatin and the novel Pt-based drug BBR3464.
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PMID:Differences in the cellular response and signaling pathways of cisplatin and BBR3464 ([[trans-PtCl(NH3)(2)]2mu-(trans-Pt(NH3)(2)(H2N(CH2)(6)-NH2)2)]4+) influenced by copper homeostasis. 1723 60

2-Methoxyestradiol (2-ME), an endogenous estrogen metabolite of 17beta-estradiol, is known to induce mitochondria-mediated apoptosis through several mechanisms. We sought to study the effect of mitochondrialy targeted hOGG1 (MTS-hOGG1) on HeLa cells exposed to 2-ME. MTS-hOGG1-expressing cells exposed to 2-ME showed increased cellular survival and had significantly less G(2)/M cell cycle arrest compared to vector-only-transfected cells. In addition, 2-ME exposure resulted in an increase in mitochondrial membrane potential, increased apoptosis, accompanied by higher activation of caspase-3, -9, cleavage of Bid to tBid and protein poly(ADP-ribose) polymerase (PARP) cleavage in HeLa cells lacking MTS-hOGG1. Fas inhibitors cerulenin or C75 inhibited 2-ME-induced caspase activation, PARP cleavage, apoptosis and reversed mitochondrial membrane hyperpolarization, thereby recapitulating the increased expression of MTS-hOGG1. Hence, MTS-hOGG1 plays an important protective role against 2-ME-mediated mitochondrial damage by blocking apoptosis induced through the Fas pathway.
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PMID:Targeting human 8-oxoguanine DNA glycosylase to mitochondria protects cells from 2-methoxyestradiol-induced-mitochondria-dependent apoptosis. 1824 24

Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies.
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PMID:Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase. 1943 22

Lack of apoptotic cell death has been implicated in malignant transformation and resistance to anticancer therapies. The promotion of apoptosis in cancer cells could potentially lead to the regression and improved prognosis of refractory colorectal cancer. Synthetic triterpenoids have shown strong antitumorigenic activity towards diverse cancer cell types, but have not been investigated for colorectal cancer. In the present study, we tested the apoptosis-inducing activity of oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CDDO-Me) and C-28 imidazole (CDDO-Im) derivatives in colorectal cancer cells lines. Cell growth/viability assay (MTS) demonstrated that colorectal cancer cells are highly sensitive to CDDO-Me at concentrations of 1.25 to 10 microM. The primary mode of tumor cell destruction was apoptosis as demonstrated by the cleavage of PARP-1, activation of procaspases -3, -8, and -9 and mitochondrial depolarization. Induction of apoptosis by CDDO-Me was associated with the inhibition of pro-survival Akt, NF-kappaB and mTOR signaling proteins and NF-kappaB-regulated anti-apoptotic Bcl-2, Bcl-xL, Bad and survivin. These studies provide rationale for clinical evaluation of CDDO-Me for the treatment of advanced chemotherapy refractory colorectal cancer.
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PMID:Synthetic triterpenoids inhibit growth, induce apoptosis and suppress pro-survival Akt, mTOR and NF-{kappa}B signaling proteins in colorectal cancer cells. 2039 97


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