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 a nuclear enzyme that signals the presence of DNA damage by catalyzing the addition of ADP-ribose units to DNA, histones, and various DNA repair enzymes and by facilitating DNA repair. PARP has been gaining increasing interest as a therapeutic target for many diseases and especially for cancer. Inhibition of PARP potentiates the activity of DNA-damaging agents, such as alkylators, platinums, topoisomerase inhibitors, and radiation in in vitro and in vivo models. In addition, tumors with DNA repair defects, such as those arising from patients with BRCA mutations, may be more sensitive to PARP inhibition. At least five different companies have now initiated oncology clinical trials with PARP inhibitors, ranging in stage from phase 0 to phase 2. This review summarizes the preclinical and clinical data currently available for these agents and some of the challenges facing the clinical development of these agents.
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PMID:Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology. 1733 79

We investigated the physical association of the DNA topoisomerase IIbeta binding protein 1 (TopBP1), involved in DNA replication and repair but also in regulation of apoptosis, with poly(ADP-ribose) polymerase-1 (PARP-1). This enzyme plays a crucial role in DNA repair and interacts with many DNA replication/repair factors. It was shown that the sixth BRCA1 C-terminal (BRCT) domain of TopBP1 interacts with a protein fragment of PARP-1 in vitro containing the DNA-binding and the automodification domains. More significantly, the in vivo interaction of endogenous TopBP1 and PARP-1 proteins could be shown in HeLa-S3 cells by co-immunoprecipitation. TopBP1 and PARP-1 are localized within overlapping regions in the nucleus of HeLa-S3 cells as shown by immunofluorescence. Exposure to UVB light slightly enhanced the interaction between both proteins. Furthermore, TopBP1 was detected in nuclear regions where poly(ADP-ribose) (PAR) synthesis takes place and is ADP-ribosylated by PARP-1. Finally, cellular (ADP-ribosyl)ating activity impairs binding of TopBP1 to Myc-interacting zinc finger protein-1 (Miz-1). The results indicate an influence of post-translational modifications of TopBP1 on its function during DNA repair.
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PMID:The DNA topoisomerase IIbeta binding protein 1 (TopBP1) interacts with poly (ADP-ribose) polymerase (PARP-1). 1734 Jun 32

Poly(ADP-ribose) polymerase 1 (PARP-1) is a DNA-binding enzyme that is activated by DNA breaks, converting them into an intracellular signal via poly(ADP-ribosyl)ation of nuclear proteins. Negatively charged polymers of ADP-ribose (PAR) attached to PARP-1 itself and histones lead to chromatin relaxation, facilitating the access of base excision/single strand break repair proteins and activating these repair enzymes. PARP inhibitors have been developed to investigate the role of PARP-1 in cell biology and to overcome DNA repair-mediated resistance of cancer cells to cytotoxic therapy. Since the early benzamide inhibitors of the 1980s PARP inhibitors, developed through structure-activity relationships and crystal structure-based drug design, that are 1,000 x more potent have been identified. These novel PARP inhibitors have been shown to enhance the antitumour activity of temozolomide (a DNA-methylating agent), topoisomerase poisons and ionising radiation in advanced pre-clinical studies and are now under clinical evaluation. PARP inhibitors can also selectively kill cells and tumours with homozygous defects in the hereditary breast cancer genes, BRCA1 and BRCA2.
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PMID:PARP inhibitor development for systemic cancer targeting. 1789 12

Myocyte injury due to myocardial reperfusion injury plays a crucial role in the pathogenesis of acute myocardial infarction even after successful coronary revascularization. Identification of compounds that reduce reperfusion-associated myocyte death is important. Therefore, we developed an in vitro model of myocardial reperfusion injury in H9c2 rat cardiomyocytes and applied a cell-based high-throughput approach to screen a standard library of pharmacologically active compounds (LOPAC) in order to identify drugs with cardioprotective effects. Oxidative stress was induced with hydrogen peroxide (H2O2) treatment, which resulted in approximately 50% reduction in cell viability. Test compounds were added at a 3-microM final concentration as a pretreatment or in a delayed fashion (30 min after the peroxide challenge in order to imitate pharmacological treatment following angioplasty). Cells were cultured for 3 or 24 h. Viability was quantitated with the methylthiazolyldiphenyl-tetrazolium bromide method. Cytotoxicity and cytoprotection were also evaluated by measuring the lactate dehydrogenase activity in the cell culture supernatant. The screening identified a number of compounds with cytoprotective action, including molecules that are known to interfere with components of DNA repair and cell cycle progression, e.g. poly(ADP-ribose) polymerase (PARP) inhibitors, topoisomerase inhibitors, and cyclin dependent kinase inhibitors, or reduce energy consumption by interfering with cardiac myofilament function. A number of dopamine D1 receptor agonists also provided significant cytoprotection at 3 h, but only three of them showed a similar effect at 24 h: chloro- and bromo-APB and chloro-PB hydrobromide. Chloro-APB hydrobromide significantly reduced peroxide-induced PARP activation in the myocytes independently of its action on dopamine D1 receptors, but lacked PARP inhibitor capacity in a cell-free PARP assay system. In conclusion, the pattern of cytoprotective drugs identified in the current assay supports the overall validity of our model system. The findings demonstrate that cytoprotective agents, including novel indirect inhibitors of cellular PARP activation can be identified with the method, chloro-APB hydrobromide being one such compound. The current experimental setting can be employed for cell-based high-throughput screening of various compound libraries.
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PMID:Oxidant-induced cardiomyocyte injury: identification of the cytoprotective effect of a dopamine 1 receptor agonist using a cell-based high-throughput assay. 1791 70

A number of anticancer drugs exert their effect by causing DNA damage and subsequent apoptosis induction. Reactive oxygen species (ROS), such as hydrogen peroxide (H(2)O(2)) and super oxide anion (O(2)(-)), participate in apoptosis and DNA damage induced by some anticancer drugs, however, the precise mechanism of apoptosis via ROS formation remains to be clarified. I investigated the mechanism of apoptosis and DNA damage induced by anticancer drugs, especially topoisomerase inhibitors, using human cultured cells. TAS-103, a topoisomerase inhibitor, induces apoptosis through DNA cleavage and subsequent H(2)O(2) generation mediated by poly (ADP-ribose) polymerase (PARP) and NAD(P)H oxidase activation. Doxorubicin (DOX), an anthracycline antibiotic and topoisomerase inhibitor, induces apoptosis through direct oxidative DNA damage leading to indirect H(2)O(2) generation mediated by PARP and NAD(P)H oxidase activation. DOX caused site-specific oxidative DNA damage in the presence of copper(II), which may contribute to apoptosis. These findings suggest that ROS formation plays important roles in apoptosis induced by anticancer drugs. Furthermore, these studies may provide an insight into the development of new effective chemotherapeutic drugs.
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PMID:[Mechanism of DNA damage and apoptosis induced by anticancer drugs through generation of reactive oxygen species]. 1797 59

2-acetyl furanonaphthoquinone (FNQ) is a naturally occurring drug with enhanced toxicity versus glucose-starved tumor cells, which frequently show topoisomerase II drug resistance. Since loss of p53 tumor suppressor function or overexpression of the anti-apoptotic bcl-2 gene can decrease susceptibility to some cancer therapies, we now investigated the effect of FNQ against genetically matched C8161 melanoma cell lines transduced to express unequal levels of Bcl-2, or engineered to harbour a functional wt p53 for comparison with dominant-negative mutant p53 R175H. Cells with differing p53 genotype showed susceptibility to FNQ. However, this response was attenuated in those overexpressing mutant p53, although a brief p53 induction was early seen in FNQ-treated wt p53 cells. Cells susceptible to FNQ showed cleavage of anti-apoptotic Mcl-1, sustained activation of the c-Jun N-terminal Kinase (p-JNK), and apoptosis-associated PARP fragmentation, all of which were counteracted in bcl-2 overexpressing cells. Suppression of JNK activation with the specific inhibitor, SP600125 also prevented FNQ-mediated cell death. Our data suggests that Bcl-2, persistent JNK phosphorylation and cleavage of anti-apoptotic Mcl-1 are key events controlling susceptibility to FNQ.
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PMID:Mcl-1 cleavage and sustained phosphorylation of c-Jun-N-terminal kinase mediate melanoma apoptosis induced by 2-acetyl furanonaphthoquinone: roles of Bcl-2 and p53. 1845 32

Ellipticine and its analogues were reported as topoisomerase II inhibitors and promising antitumor agents. In this work, we showed that the growth of human non-small-cell-lung-cancer (NSCLC) epithelial cells A549 can be inhibited by ellipticine. The inhibitory effect was reverted by PI3K inhibitors. The sub-G(1) phase cells after ellipticine treatment appeared at the expense of those that accumulated first at S- and G(2)/M phases during the early stage of treatment. We showed that the progression leading to cell death was impaired by wortmannin, which reverted apoptosis by retaining cells at S- and G(2)/M transition states. The characteristic apoptosis marker p53 activation after treatment appeared first followed by poly(ADP-ribose)polymerase (PARP) fragmentation. They disappeared upon co-treatment with wortmannin and the apoptotic phenotype reversed. Furthermore, ellipticine regulated endogenous survival signaling by up-regulating phosphorylated Akt that returned to its basal level later. Furthermore, ellipticine induced nucleus translocalization of p53 and Akt and recruitment of autophagosomes. The autophagic-related cell death was interfered by wortmannin and the suppressed growth reverted. The Akt-related cell death also occurred in p53-deficient cells with stable expression of exogenous p53. The work showed that ellipticine-induced cytotoxicity in NSCLC cells was achieved through autophagy and apoptotic death as a result of Akt-modulation. Being a topoisomerase II inhibitor, ellipticine proved a regulator in autophagy-related cell death through corporation of p53 and Akt.
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PMID:Ellipticine-induced apoptosis depends on Akt translocation and signaling in lung epithelial cancer cells. 2759 91

In the presence of ERbeta, trans-hydroxytamoxifen (TOT) protects cells against 17beta-estradiol (E(2))-induced oxidative DNA damage (ODD) and this correlates with increased expression of the antioxidative enzyme quinone reductase (QR). Here, we investigate the molecular mechanism responsible for ERbeta-mediated protection against ODD. We observe constitutive interaction between ERbeta and the novel protein hPMC2. Using a combination of breast epithelial cell lines that are either positive or negative for ERalpha, we demonstrate TOT-dependent recruitment of both ERbeta and hPMC2 to the EpRE (electrophile response element)-regulated antioxidative enzyme QR. We further demonstrate TOT-dependent corecruitment of the coactivators Nrf2, PARP-1 (poly (ADP-ribose) polymerase 1) and topoisomerase IIbeta, both in the presence and absence of ERalpha. However, absence of either ERbeta or hPMC2 results in nonrecruitment of PARP-1 and topoisomerase IIbeta, loss of antioxidative enzyme induction and attenuated protection against ODD by TOT even in the presence of Nrf2 and ERalpha. These findings indicate minor role for Nrf2 and ERalpha in TOT-dependent antioxidative gene regulation. However, downregulation of PARP-1 attenuates TOT-dependent antioxidative gene induction. We conclude that ERbeta and hPMC2 are required for TOT-dependent recruitment of coactivators such as PARP-1 to the EpRE resulting in the induction of antioxidative enzymes and subsequent protection against ODD.
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PMID:hPMC2 is required for recruiting an ERbeta coactivator complex to mediate transcriptional upregulation of NQO1 and protection against oxidative DNA damage by tamoxifen. 1866 60

Many established cancer therapies involve DNA-damaging chemotherapy or radiotherapy. The DNA repair capacity of the tumor represents a common mechanism used by cancer cells to survive DNA-damaging therapy. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that is activated by DNA damage and has critical roles in DNA repair. Inhibition of PARP potentiates the activity of DNA-damaging agents such as temozolomide, topoisomerase inhibitors and radiation in both in vitro and in vivo preclinical models. Recently, several PARP inhibitors have entered clinical trials either as single agents or in combination with DNA-damaging chemotherapy. Because PARP inhibitors are not cytotoxic, a biomarker assay is useful to guide the selection of an optimal biological dose. We set out to develop an assay that enables us to detect 50% PAR reduction in human tumors with 80% power in a single-plate assay while assuring no more than a 10% false-positive rate. We have developed and optimized an enzyme-linked immunosorbent assay (ELISA) to measure PARP activity that meets the above-mentioned criterion. This robust assay is able to detect PAR levels of 30-2000 pg/ml in both tumor and peripheral blood monocyte samples. In a B16F10 mouse syngeneic tumor model, PARP inhibitor ABT-888 potentiates the effect of temozolomide in suppressing tumor growth, and PARP activity is greatly reduced by ABT-888 at efficacious doses. In summary, the ELISA assay described here is suitable for biomarker studies in clinical trials of PARP inhibitors.
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PMID:An enzyme-linked immunosorbent poly(ADP-ribose) polymerase biomarker assay for clinical trials of PARP inhibitors. 1867 9

Doxorubicin is an important component of combination therapy for muscle-invasive urinary bladder cancer. Treatment with this topoisomerase II poison is able to interfere with cell cycle progression and lead to cancer cell death. Using FACS analysis, Western immunoblotting and semi-quantitative RT-PCR, we studied the effects of doxorubicin on cell cycle progression and apoptosis, and also explored the possibility of using groups of genes as biomarkers of prognosis and/or response to doxorubicin treatment in human urinary bladder cancer cells. Doxorubicin induced dose-dependent G2/M and/or G1/S cell cycle arrest, followed by grade- and dose-dependent reduction in the amount of the cytosolic trimeric form of FasL, activation of Caspase-8, Caspase-9, Caspase-3, cleavage of PARP, Lamin A/C, Bcl-XL/S and interestingly Hsp90, and finally cell death. Data presented here also suggest the use of the expression patterns of Cyclin-E2, Cyclin-F, p63, p73, FasL, TRAIL, Tweak, Tweak-R, XAF-1, OPG and Bok genes for identification of the differentiation grade, and Cyclin-B2, GADD45A, p73, FasL, Bik, Bim, TRAIL, Fas, Tweak-R, XAF-1, Bcl-2, Survivin, OPG, DcR2 and Bcl-XL genes for the detection of response to doxorubicin in human bladder cancer cells.
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PMID:Grade-dependent effects on cell cycle progression and apoptosis in response to doxorubicin in human bladder cancer cell lines. 1908 86


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