Specific Inhibitors of Poly(ADP- Ribose) Synthetase

Banasik, Marek; Komura, Hajime; Ueda, Kunihiro

doi:10.1007/978-1-4419-8718-1_61

Cited by 163 publications

(230 citation statements)

References 12 publications

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“…In our HBMEC model of HX/RO that results in a 30% to 40% loss of cell viability, treatment with 3-AB and 4-AN, two mechanistically distinct PARP-1 inhibitors (Banasik et al, 1992;Schlicker et al, 1999;Thiemermann et al, 1997), during HX/RO dosedependently blocked AIF translocation and reduced apoptotic cell death, supporting the concept that early PARP-1 activation is an upstream trigger of mitochondrial AIF release in cerebral endothelium.…”

Section: Discussionsupporting

confidence: 68%

Cerebral Endothelial Cell Apoptosis after Ischemia—Reperfusion: Role of PARP Activation and AIF Translocation

Zhang

Park

et al. 2005

J Cereb Blood Flow Metab

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Cerebral ischemia-reperfusion leads to vascular dysfunction characterized by endothelial cell injury or death. In the present study, we used an in vitro model to elucidate mechanisms of human brain microvascular endothelial cell (HBMEC) injury after episodic ischemia-reperfusion. Near-confluent HBMEC cultures were exposed to intermittent hypoxia-reoxygenation (HX/RO) and, at different recovery time points, cell viability was assessed by the MTT assay, apoptotic death by fluorescence microscopy of terminal deoxynucleotidyl transferase-mediated 2 0 -deoxyuridine 5 0 -triphosphatebiotin nick end labeling (TUNEL)-positive cells, and nuclear translocation of apoptosis-inducing factor (AIF) and cleavage of poly(ADP-ribose) polymerase-1 (PARP-1) by immunoblotting of subcellular fractions. Reductions in HBMEC viability were proportional to the number of HX/RO cycles, and not the total duration of hypoxia. Using four cycles of 1-h HX with 1 h of intervening normoxic RO, cell viability was reduced 30% to 40% between 12 and 48 h. Treatment with the PARP-1 inhibitors 3-aminobenzamide or 4-amino-1,8-naphthalimide during the insult improved HBMEC viability at 24 h after insult, and resulted in dose-dependent reductions in TUNEL-positivity at 16 h after insult, but not if these treatments were delayed by 4 h. HX/RO-induced increases in nuclear AIF translocation, as well as PARP-1 cleavage, were also reduced dose-dependently at 4 h after insult by the inhibitors. The caspase inhibitor z-VAD-fmk blocked PARP-1 cleavage, but did not affect AIF translocation and was only modestly cytoprotective. These findings indicate that PARP-1 activation and a PARP-1-dependent, caspase-independent, nuclear translocation of AIF contribute to apoptotic cerebral endothelial cell death after ischemia-reperfusion, underscoring the potential for ischemic microvascular protection by inhibiting PARP activation or preventing AIF translocation.

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Section: Discussionsupporting

confidence: 68%

Cerebral Endothelial Cell Apoptosis after Ischemia—Reperfusion: Role of PARP Activation and AIF Translocation

Zhang

Park

et al. 2005

J Cereb Blood Flow Metab

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“…Coumarin-containing Molecules-A large number of molecules chosen mostly among proposed inhibitors of characterized eukaryotic ADP-ribosyltransferases (33,34) were screened for inhibitory activity in the BFA-dependent mono-ADP-ribosylation assay. In an initial survey, the antibiotic novobiocin (34) was found to be the most potent, with an effect on the BFA-dependent mono-ADP-ribosylation of GAPDH at 350 M. Novobiocin contains the coumarin moiety also present in many inhibitors of the NADH-binding enzyme diaphorase (46).…”

Section: Chemical Inhibitors Of In Vitro Bfa-dependent Mono-adp-ribosmentioning

confidence: 99%

“…This suggests that the same (or very similar) BFA-binding components may be involved in the two BFA-induced events. Second, nonspecific inhibitors of mono-ADP-ribosylation such as nicotinamide (33,34) can reduce the effects of the toxin on the morphology of the Golgi complex (35). It is therefore of interest to develop a set of specific inhibitors of BFA-induced mono-ADP-ribosylation as they would greatly help to define the cellular role of this reaction.…”

mentioning

confidence: 99%

Characterization of Chemical Inhibitors of Brefeldin A-activated Mono-ADP-ribosylation

Weigert

Colanzi

Mirоnоv

et al. 1997

Journal of Biological Chemistry

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Brefeldin A, a toxin inhibitor of vesicular traffic, induces the selective mono-ADP-ribosylation of two cytosolic proteins, glyceraldehyde-3-phosphate dehydrogenase and the novel GTP-binding protein BARS-50. Here, we have used a new quantitative assay for the characterization of this reaction and the development of specific pharmacological inhibitors. Mono-ADP-ribosylation is activated by brefeldin A with an EC 50 of 17.0 ؎ 3.1 g/ml, but not by biologically inactive analogs including a brefeldin A stereoisomer. Brefeldin A acts by increasing the V max of the reaction, whereas it does not influence the K m of the enzyme for NAD ؉ (154 ؎ 13 M). The enzyme is an integral membrane protein present in most tissues and is modulated by Zn 2؉ , Cu 2؉ , ATP (but not by other nucleotides), pH, temperature, and ionic strength. To identify inhibitors of the reaction, a large number of drugs previously tested as blockers of bacterial ADPribosyltransferases were screened. Two classes of molecules, one belonging to the coumarin group (dicumarol, coumermycin A 1 , and novobiocin) and the other to the quinone group (ilimaquinone, benzoquinone, and naphthoquinone), rather potently and specifically inhibited brefeldin A-dependent mono-ADP-ribosylation. When tested in living cells, these molecules antagonized the tubular reticular redistribution of the Golgi complex caused by brefeldin A at concentrations similar to those active in the mono-ADP-ribosylation assay in vitro, suggesting a role for mono-ADP-ribosylation in the cellular actions of brefeldin A.Mono-ADP-ribosylation is a post-translational modification of proteins whereby the adenosine 5Ј-diphosphoribose moiety of NAD ϩ is transferred to one of a number of amino acid residues (1, 2). Several well characterized mono-ADP-ribosylation reactions are catalyzed by bacterial toxins and result in the permanent modification of GTPases with key regulatory functions in cellular processes (1, 2). Similar reactions are also catalyzed by eukaryotic enzymes, but their cellular significance, despite recent advances (3-5), is less well understood. Recently, we have reported that brefeldin A (BFA), 1 a fungal toxin metabolite of palmitic acid (6) with potent inhibitory effects on intracellular membrane traffic (7), stimulates the selective mono-ADP-ribosylation of two cytosolic proteins of 38 and 50 kDa in mammalian cells (8). The 50-kDa substrate (BARS-50; see Ref. 9) binds GTP and is regulated by ␤␥-subunits of trimeric G proteins; it has therefore been proposed to be a novel G protein involved in membrane transport (9). The p38 substrate is glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a multifunctional protein involved in several cellular processes (10 -16). These observations have raised the question as to whether some of the cellular effects of BFA might be mediated by mono-ADP-ribosylation.The cellular actions of BFA are multiple and complex. BFA selectively blocks constitutive protein secretion and causes a rapid and extensive disruption of the Golgi apparatus consisting of the ...

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“…Five of the compounds have already been described as tankyrase inhibitors and have also been characterized using protein crystallography: 17 (PJ-34; ARTD5 IC50 570 nM), 8,9 21 (Olaparib; ARTD5 IC50 1500 nM), 10,11 23 (XAV939; ARTD5 IC50 11 nM), 12,13 26 (IWR-1; ARTD5 IC50 130 nM), 10 and 32 (flavone; ARTD5 330 nM). 7,14 In this study, we characterized the binding mode of the four additional compounds using X-ray crystallography: 10 (EB-47), 15 16 (phenanthridinone), 16 18 (TIQ-A), 17 and 29 (rucaparib). 18 As 17 (PJ-34) has also been reported to bind to a distinct adenosine binding groove of the catalytic domain we included this compound in further studies.…”

mentioning

confidence: 99%

Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors

Haikarainen

Narwal

Joensuu

et al. 2013

ACS Med. Chem. Lett.

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Tankyrases, an enzyme subfamily of human poly(ADP-ribosyl)polymerases, are potential drug targets especially against cancer. We have evaluated inhibition of tankyrases by known PARP inhibitors and report five cocrystal structures of the most potent compounds in complex with human tankyrase 2. The inhibitors include the small general PARP inhibitors Phenanthridinone, PJ-34, and TIQ-A as well as the more advanced inhibitors EB-47 and rucaparib. The compounds anchor to the nicotinamide subsite of tankyrase 2. Crystal structures reveal flexibility of the ligand binding site with implications for drug development against tankyrases and other ADP-ribosyltransferases. EB-47 mimics the substrate NAD + and extends from the nicotinamide to the adenosine subsite. The clinical ARTD1 inhibitor candidate rucaparib was the most potent tankyrase inhibitor identified (24 and 14 nM for tankyrases), which indicates that inhibition of tankyrases would affect the cellular responses of this compound.

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Specific Inhibitors of Poly(ADP- Ribose) Synthetase

Cited by 163 publications

References 12 publications

Cerebral Endothelial Cell Apoptosis after Ischemia—Reperfusion: Role of PARP Activation and AIF Translocation

Cerebral Endothelial Cell Apoptosis after Ischemia—Reperfusion: Role of PARP Activation and AIF Translocation

Characterization of Chemical Inhibitors of Brefeldin A-activated Mono-ADP-ribosylation

Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors

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