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19 results on '"Rozanska, Agata"'

3. The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

Author

Barret, Didier, Albouys, Vincent, Herder, Jan-Willem den, Piro, Luigi, Cappi, Massimo, Huovelin, Juhani, Kelley, Richard, Mas-Hesse, J. Miguel, Paltani, Stéphane, Rauw, Gregor, Rozanska, Agata, Svoboda, Jiri, Wilms, Joern, Yamasaki, Noriko, Audard, Marc, Bandler, Simon, Barbera, Marco, Barcons, Xavier, Bozzo, Enrico, Ceballos, Maria Teresa, Charles, Ivan, Costantini, Elisa, Dauser, Thomas, Decourchelle, Anne, Duband, Lionel, Duval, Jean-Marc, Fiore, Fabrizio, Gatti, Flavio, Goldwurm, Andrea, Hartog, Roland den, Jackson, Brian, Jonker, Peter, Kilbourne, Caroline, Korpela, Seppo, Macculi, Claudio, Mendez, Mariano, Mitsuda, Kazuhisa, Molendi, Silvano, Pajot, François, Pointecouteau, Etienne, Porter, Frederick, Pratt, Gabriel W., Prêle, Damien, Ravera, Laurent, Sato, Kosuke, Schaye, Joop, Shinozaki, Keisuke, Skup, Konrad, Soucek, Jan, Thibert, Tanguy, Vink, Jacco, Webb, Natalie, Chaoul, Laurence, Raulin, Desi, Simionescu, Aurora, Torrejon, Jose Miguel, Acero, Fabio, Branduardi-Raymont, Graziella, Ettori, Stefano, Finoguenov, Alexis, Grosso, Nicolas, Kaastra, Jelle, Mazzotta, Pasquale, Miller, Jon, Miniutti, Giovanni, Nicastro, Fabrizio, Sciortino, Salvatore, Yamaguchi, Hiroya, Beaumont, Sophie, Cucchetti, Edoardo, D’Andrea, Matteo, Eckart, Megan, Ferrando, Philippe, Kammoun, Elias, Lotti, Simone, Mesnager, Jean-Michel, Natalucci, Lorenzo, Peille, Philippe, de Plaa, Jelle, Ardellier, Florence, Argan, Andrea, Bellouard, Elise, Carron, Jérôme, Cavazzuti, Elisabetta, Fiorini, Mauro, Khosropanah, Pourya, Martin, Sylvain, Perry, James, Pinsard, Frederic, Pradines, Alice, Rigano, Manuela, Roelfsema, Peter, Schwander, Denis, Torrioli, Guido, Ullom, Joel, Vera, Isabel, Villegas, Eduardo Medinaceli, Zuchniak, Monika, Brachet, Frank, Cicero, Ugo Lo, Doriese, William, Durkin, Malcom, Fioretti, Valentina, Geoffray, Hervé, Jacques, Lionel, Kirsch, Christian, Smith, Stephen, Adams, Joseph, Gloaguen, Emilie, Hoogeveen, Ruud, van der Hulst, Paul, Kiviranta, Mikko, van der Kuur, Jan, Ledot, Aurélien, van Leeuwen, Bert-Joost, van Loon, Dennis, Lyautey, Bertrand, Parot, Yann, Sakai, Kazuhiro, van Weers, Henk, Abdoelkariem, Shariefa, Adam, Thomas, Adami, Christophe, Aicardi, Corinne, Akamatsu, Hiroki, Alonso, Pablo Eleazar Merino, Amato, Roberta, André, Jérôme, Angelinelli, Matteo, Anon-Cancela, Manuel, Anvar, Shebli, Atienza, Ricardo, Attard, Anthony, Auricchio, Natalia, Balado, Ana, Bancel, Florian, Barusso, Lorenzo Ferrari, Bascuñan, Arturo, Bernard, Vivian, Berrocal, Alicia, Blin, Sylvie, Bonino, Donata, Bonnet, François, Bonny, Patrick, Boorman, Peter, Boreux, Charles, Bounab, Ayoub, Boutelier, Martin, Boyce, Kevin, Brienza, Daniele, Bruijn, Marcel, Bulgarelli, Andrea, Calarco, Simona, Callanan, Paul, Campello, Alberto Prada, Camus, Thierry, Canourgues, Florent, Capobianco, Vito, Cardiel, Nicolas, Castellani, Florent, Cheatom, Oscar, Chervenak, James, Chiarello, Fabio, Clerc, Laurent, Clerc, Nicolas, Cobo, Beatriz, Coeur-Joly, Odile, Coleiro, Alexis, Colonges, Stéphane, Corcione, Leonardo, Coriat, Mickael, Coynel, Alexandre, Cuttaia, Francesco, D’Ai, Antonino, D’anca, Fabio, Dadina, Mauro, Daniel, Christophe, Dauner, Lea, DeNigris, Natalie, Dercksen, Johannes, DiPirro, Michael, Doumayrou, Eric, Dubbeldam, Luc, Dupieux, Michel, Dupourqué, Simon, Durand, Jean Louis, Eckert, Dominique, Eiriz, Valvanera, Ercolani, Eric, Etcheverry, Christophe, Finkbeiner, Fred, Fiocchi, Mariateresa, Fossecave, Hervé, Franssen, Philippe, Frericks, Martin, Gabici, Stefano, Gant, Florent, Gao, Jian-Rong, Gastaldello, Fabio, Genolet, Ludovic, Ghizzardi, Simona, Gil, Ma Angeles Alcacera, Giovannini, Elisa, Godet, Olivier, Gomez-Elvira, Javier, Gonzalez, Raoul, Gonzalez, Manuel, Gottardi, Luciano, Granat, Dolorès, Gros, Michel, Guignard, Nicolas, Hieltjes, Paul, Hurtado, Adolfo Jesús, Irwin, Kent, Jacquey, Christian, Janiuk, Agnieszka, Jaubert, Jean, Jiménez, Maria, Jolly, Antoine, Jourdan, Thierry, Julien, Sabine, Kedziora, Bartosz, Korb, Andrew, Kreykenbohm, Ingo, König, Ole, Langer, Mathieu, Laudet, Philippe, Laurent, Philippe, Laurenza, Monica, Lesrel, Jean, Ligori, Sebastiano, Lorenz, Maximilian, Luminari, Alfredo, Maffei, Bruno, Maisonnave, Océane, Marelli, Lorenzo, Massonet, Didier, Maussang, Irwin, Melchor, Alejandro Gonzalo, Le Mer, Isabelle, Millan, Francisco Javier San, Millerioux, Jean-Pierre, Mineo, Teresa, Minervini, Gabriele, Molin, Alexeï, Monestes, David, Montinaro, Nicola, Mot, Baptiste, Murat, David, Nagayoshi, Kenichiro, Nazé, Yaël, Noguès, Loïc, Pailot, Damien, Panessa, Francesca, Parodi, Luigi, Petit, Pascal, Piconcelli, Enrico, Pinto, Ciro, Plaza, Jose Miguel Encinas, Plaza, Borja, Poyatos, David, Prouvé, Thomas, Ptak, Andy, Puccetti, Simonetta, Puccio, Elena, Ramon, Pascale, Reina, Manuel, Rioland, Guillaume, Rodriguez, Louis, Roig, Anton, Rollet, Bertrand, Roncarelli, Mauro, Roudil, Gilles, Rudnicki, Tomasz, Sanisidro, Julien, Sciortino, Luisa, Silva, Vitor, Sordet, Michael, Soto-Aguilar, Javier, Spizzi, Pierre, Surace, Christian, Sánchez, Miguel Fernández, Taralli, Emanuele, Terrasa, Guilhem, Terrier, Régis, Todaro, Michela, Ubertini, Pietro, Uslenghi, Michela, de Vaate, Jan Geralt Bij, Vaccaro, Davide, Varisco, Salvatore, Varnière, Peggy, Vibert, Laurent, Vidriales, María, Villa, Fabrizio, Vodopivec, Boris Martin, Volpe, Angela, de Vries, Cor, Wakeham, Nicholas, Walmsley, Gavin, Wise, Michael, de Wit, Martin, and Woźniak, Grzegorz

Published
2023
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6. pRB-Depleted Pluripotent Stem Cell Retinal Organoids Recapitulate Cell State Transitions of Retinoblastoma Development and Suggest an Important Role for pRB in Retinal Cell Differentiation.

Author

Rozanska, Agata, Cerna-Chavez, Rodrigo, Queen, Rachel, Collin, Joseph, Zerti, Darin, Dorgau, Birthe, Beh, Chia Shyan, Davey, Tracey, Coxhead, Jonathan, Hussain, Rafiqul, Al-Aama, Jumana, Steel, David H, Benvenisty, Nissim, Armstrong, Lyle, Parulekar, Manoj, and Lako, Majlinda

Published
2022
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9. The human RNA-binding protein RBFA promotes the maturation of the mitochondrial ribosome.

Author

Rozanska, Agata, Richter-Dennerlein, Ricarda, Rorbach, Joanna, Fei Gao, Lewis, Richard J., Chrzanowska-Lightowlers, Zofia M., and Lightowlers, Robert N.

Subjects
*RIBOSOMES, *MITOCHONDRIAL RNA, *CARRIER proteins, *MITOCHONDRIAL proteins, *ADENINE
Abstract

Accurate assembly and maturation of human mitochondrial ribosomes is essential for synthesis of the 13 polypeptides encoded by the mitochondrial genome. This process requires the correct integration of 80 proteins, 1 mt (mitochondrial)-tRNA and 2 mt-rRNA species, the latter being post-transcriptionally modified at many sites. Here, we report that human ribosome-binding factor A (RBFA) is a mitochondrial RNA-binding protein that exerts crucial roles in mitoribosome biogenesis. Unlike its bacterial orthologue, RBFA associates mainly with helices 44 and 45 of the 12S rRNA in the mitoribosomal small subunit to promote dimethylation of two highly conserved consecutive adenines. Characterization of RBFA-depleted cells indicates that this dimethylation is not a prerequisite for assembly of the small ribosomal subunit. However, the RBFA-facilitated modification is necessary for completing mt-rRNA maturation and regulating association of the small and large subunits to form a functional monosome implicating RBFA in the quality control of mitoribosome formation. [ABSTRACT FROM AUTHOR]

Published
2017
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11. Mitochondrial protein synthesis: Figuring the fundamentals, complexities and complications, of mammalian mitochondrial translation.

Author

Lightowlers, Robert N., Rozanska, Agata, and Chrzanowska-Lightowlers, Zofia M.

Subjects
*MITOCHONDRIAL proteins, *PROTEIN synthesis, *MAMMAL genetics, *GENETIC translation, *POLYPEPTIDES, *PHOSPHORYLATION, *GENE expression
Abstract

Mitochondrial protein synthesis is essential for all mammals, being responsible for providing key components of the oxidative phosphorylation complexes. Although only thirteen different polypeptides are made, the molecular details of this deceptively simple process remain incomplete. Central to this process is a non-canonical ribosome, the mitoribosome, which has evolved to address its unique mandate. In this review, we integrate the current understanding of the molecular aspects of mitochondrial translation with recent advances in structural biology. We identify numerous key questions that we will need to answer if we are to increase our knowledge of the molecular mechanisms underlying mitochondrial protein synthesis. [ABSTRACT FROM AUTHOR]

Published
2014
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12. Mutations in mitochondrial ribosomal protein MRPL12 leads to growth retardation, neurological deterioration and mitochondrial translation deficiency.

Author

Serre, Valérie, Rozanska, Agata, Beinat, Marine, Chretien, Dominique, Boddaert, Nathalie, Munnich, Arnold, Rötig, Agnès, and Chrzanowska-Lightowlers, Zofia M.

Subjects
*RIBOSOMAL proteins, *MITOCHONDRIAL pathology, *DWARFISM, *GENETIC mutation, *EUBACTERIALES
Abstract

Abstract: Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases and are associated with a wide range of clinical symptoms. We report a subject, born to consanguineous parents, with growth retardation and neurological deterioration. Multiple respiratory chain deficiency was found in muscle and fibroblasts of the subject as well as abnormal assembly of complexes I and IV. A microsatellite genotyping of the family members detected only one region of homozygosity on chromosome 17q24.2–q25.3 in which we focused our attention to genes involved in mitochondrial translation. We sequenced MRPL12, encoding the mitochondrial ribosomal protein L12 and identified a c.542C>T transition in exon 5 changing a highly conserved alanine into a valine (p.Ala181Val). This mutation resulted in a decreased steady-state level of MRPL12 protein, with altered integration into the large ribosomal subunit. Moreover, an overall mitochondrial translation defect was observed in the subject's fibroblasts with a significant reduction of synthesis of COXI, COXII and COXIII subunits. Modeling of MRPL12 shows Ala181 positioned in a helix potentially involved in an interface of interaction suggesting that the p.Ala181Val change might be predicted to alter interactions with the elongation factors. These results contrast with the eubacterial orthologues of human MRPL12, where L7/L12 proteins do not appear to have a selective effect on translation. Therefore, analysis of the mutated version found in the subject presented here suggests that the mammalian protein does not function in an entirely analogous manner to the eubacterial L7/L12 equivalent. [Copyright &y& Elsevier]

Published
2013
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13. Thermal Conduction and Thermal Instability in the Transition layer between an Accretion Disc and Corona.

Author

Rozanska, Agata

Subjects
*ACCRETION (Astrophysics), *ASTROPHYSICS
Abstract

ABSTRACT We study the vertical structure of the transition layer between am accretion disc and corona in the context of the existence of two-phase medium in thermally unstable regions. The disc is illuminated by hard X-ray radiation and satisfies the condition of hydrostatic equilibrium. We take into account the energy exchange between hot corona (∼ 10[sup 8] K) and cool disc (∼ 10[sup 4] K) through the radiative processes and due to thermal conduction. We make local stability analysis of the case with conductivity and we conclude that thermal conduction does not suppress thermal instability. In spite of continuous temperature profile T(τ) there are regions with strong temperature gradient where spontaneous perturbations can lead to cloud condensation in the transition layer. We determine the minimum size λTC of such a perturbation. [ABSTRACT FROM AUTHOR]

Published
1999

14. The Pseudouridine Synthase RPUSD4 Is an Essential Component of Mitochondrial RNA Granules.

Author

Zaganelli, Sofia, Rebelo-Guiomar, Pedro, Maundrell, Kinsey, Rozanska, Agata, Pierredon, Sandra, Powell, Christopher A., Jourdain, Alexis A., Hulo, Nicolas, Lightowlers, Robert N., Chrzanowska-Lightowlers, Zofia M., Minczuk, Michal, and Martinou, Jean-Claude

Subjects
*PSEUDOURIDINE synthases, *MITOCHONDRIAL RNA, *GENE expression, *MOLECULAR genetics, *MOLECULAR biology
Abstract

Mitochondrial gene expression is a fundamental process that is largely dependent on nuclear-encoded proteins. Several steps of mitochondrial RNA processing and maturation, including RNA post-transcriptional modification, appear to be spatially organized into distinct foci, which we have previously termed mitochondrial RNA granules (MRGs). Although an increasing number of proteins have been localized to MRGs, a comprehensive analysis of the proteome of these structures is still lacking. Here, we have applied a microscopy-based approach that has allowed us to identify novel components of the MRG proteome. Among these, we have focused our attention on RPUSD4, an uncharacterized mitochondrial putative pseudouridine synthase. We show that RPUSD4 depletion leads to a severe reduction of the steady-state level of the 16S mitochondrial (mt) rRNA with defects in the biogenesis of the mitoribosome large subunit and consequently in mitochondrial translation. We report that RPUSD4 binds 16S mt-rRNA, mttRNA Met, and mt-tRNAPhe, and we demonstrate that it is responsible for pseudouridylation of the latter. These data provide new insights into the relevance of RNA pseudouridylation in mitochondrial gene expression. [ABSTRACT FROM AUTHOR]

Published
2017
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16. Scientific Business Abstracts.

Author

Cooles F, Vidal-Pedrola G, Naamane N, Pratt A, Barron-Millar B, Anderson A, Hilkens C, Casement J, Bondet V, Duffy D, Zhang F, Shukla R, Isaacs J, Little M, Payne M, Coupe N, Fairfax B, Taylor CA, Mackay S, Milotay G, Bos S, Hunter B, Mcdonald D, Merces G, Sheldon G, Pradère P, Majo J, Pulle J, Vanstapel A, Vanaudenaerde BM, Vos R, Filby AJ, Fisher AJ, Collier J, Lambton J, Suomi F, Prigent M, Guissart C, Erskine D, Rozanska A, Mccorvie T, Trimouille A, Imam A, Hobson E, Mccullagh H, Frengen E, Misceo D, Bjerre A, Smeland M, Klingenberg C, Alkuraya F, Mcfarland R, Alston C, Yue W, Legouis R, Koenig M, Lako M, Mcwilliams T, Oláhová M, Taylor R, Newman W, Harkness R, McDermott J, Metcalfe K, Khan N, Macken W, Pitceathly R, Record C, Maroofian R, Sabir A, Santra S, Urquhart J, Demain L, Byers H, Beaman G, Yue W, Taylor R, Durmusalioglu E, Atik T, Isik E, Cogulu O, Reunert J, Marquardt T, Ryba L, Buchert-Lo R, Haack T, Lassuthova P, Polavarapu K, Lochmuller H, Horvath R, Jamieson P, Reilly M, O'Keefe R, Boggan R, Ng YS, Franklin I, Alston C, Blakely E, Büchner B, Bugiardini E, Colclough K, Feeney C, Hanna M, Hattersley A, Klopstock T, Kornblum C, Mancuso M, Patel K, Pitceathly R, Pizzamiglio C, Prokisch H, Schäfer J, Schaefer A, Shepherd M, Thaele A, Thomas R, Turnbull D, Gorman G, Woodward C, McFarland R, Taylor R, Cordell H, Pickett S, Tsilifis C, Pearce M, Gennery A, Daly A, Darlay R, Zatorska M, Worthington S, Anstee Q, Cordell H, Reeves H, Nizami S, Mauricio-Muir J, McCain M, Singh R, Wordsworth J, Kadharusman M, Watson R, Masson S, McPherson S, Burt A, Tiniakos D, Littler P, Nsengimana J, Zhang S, Mann D, Jamieson D, Leslie J, Shukla R, Wilson C, Betts J, Croall I, Hoggard N, Bennett J, Naamane N, Hollingsworth KG, Pratt AG, Egail M, Feeney C, Di Leo V, Taylor RW, Dodds R, Anderson AE, Sayer AA, Isaacs JD, McCracken C, Condurache DG, Szabo L, Elghazaly H, Walter F, Meade A, Chakraverty R, Harvey N, Manisty C, Petersen S, Neubauer S, Raisi-Estabragh Z, Allen L, Taylor P, Carlsson A, Hagopian W, Hedlund E, Hill A, Jones A, Ludvigsson J, Onengut-Gumuscu S, Redondo M, Rich S, Gillespie K, Dayan C, Oram R, Resteu A, Wonders K, Schattenberg J, Straub B, Ekstedt M, Berzigotti A, Geier A, Francque S, Driessen A, Boursier J, Yki-Jarvinen H, Arola J, Aithal G, Holleboom A, Verheij J, Yunis C, Trylesinski A, Papatheodoridis G, Petta S, Romero-Gomez M, Bugianesi E, Paradis V, Ratziu V, Tiniakos D, Anstee Q, Burton J, Ciminata G, Geue C, Quinn T, Glover E, Morais M, Reynolds G, Denby L, Ali S, Lennon R, Sheerin N, Yang F, Zounemat-Kermani N, Dixey P, Adcock IM, Bloom CI, Chung KF, Govaere O, Hasoon M, Alexander L, Cockell S, Tiniakos D, Ekstedt M, Schattenberg JM, Boursier J, Bugianesi E, Ratziu V, Daly AK, and Anstee QM

Published
2024
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17. Translation termination in human mitochondrial ribosomes.

Author

Richter R, Pajak A, Dennerlein S, Rozanska A, Lightowlers RN, and Chrzanowska-Lightowlers ZM

Subjects
Codon, DNA, Mitochondrial genetics, Genetic Code, Humans, Ribosomes genetics, DNA, Mitochondrial metabolism, Mitochondria genetics, Mitochondria metabolism, Peptide Chain Termination, Translational, Protein Biosynthesis, Ribosomes metabolism
Abstract

Mitochondria are ubiquitous and essential organelles for all nucleated cells of higher eukaryotes. They contain their own genome [mtDNA (mitochondrial DNA)], and this autosomally replicating extranuclear DNA encodes a complement of genes whose products are required to couple oxidative phosphorylation. Sequencing of this human mtDNA more than 20 years ago revealed unusual features that included a modified codon usage. Specific deviations from the standard genetic code include recoding of the conventional UGA stop to tryptophan, and, strikingly, the apparent recoding of two arginine triplets (AGA and AGG) to termination signals. This latter reassignment was made because of the absence of cognate mtDNA-encoded tRNAs, and a lack of tRNAs imported from the cytosol. Each of these codons only occurs once and, in both cases, at the very end of an open reading frame. The presence of both AGA and AGG is rarely found in other mammals, and the molecular mechanism that has driven the change from encoding arginine to dictating a translational stop has posed a challenging conundrum. Mitochondria from the majority of other organisms studied use only UAA and UAG, leaving the intriguing question of why human organelles appear to have added the complication of a further two stop codons, AGA and AGG, or have they? In the present review, we report recent data to show that mammalian mitochondria can utilize a -1 frameshift such that only the standard UAA and UAG stop codons are required to terminate the synthesis of all 13 polypeptides.

Published
2010
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18. Human ERAL1 is a mitochondrial RNA chaperone involved in the assembly of the 28S small mitochondrial ribosomal subunit.

Author

Dennerlein S, Rozanska A, Wydro M, Chrzanowska-Lightowlers ZM, and Lightowlers RN

Subjects
Blotting, Northern, Cell Line, GTP-Binding Proteins genetics, HeLa Cells, Humans, Mitochondrial Proteins biosynthesis, Molecular Chaperones genetics, Molecular Chaperones metabolism, RNA genetics, RNA Interference, RNA Stability, RNA, Mitochondrial, RNA, Ribosomal genetics, RNA, Ribosomal metabolism, RNA, Ribosomal, 28S genetics, RNA-Binding Proteins genetics, GTP-Binding Proteins metabolism, RNA metabolism, RNA, Ribosomal, 28S metabolism, RNA-Binding Proteins metabolism
Abstract

The bacterial Ras-like protein Era has been reported previously to bind 16S rRNA within the 30S ribosomal subunit and to play a crucial role in ribosome assembly. An orthologue of this essential GTPase ERAL1 (Era G-protein-like 1) exists in higher eukaryotes and although its exact molecular function and cellular localization is unknown, its absence has been linked to apoptosis. In the present study we show that human ERAL1 is a mitochondrial protein important for the formation of the 28S small mitoribosomal subunit. We also show that ERAL1 binds in vivo to the rRNA component of the small subunit [12S mt (mitochondrial)-rRNA]. Bacterial Era associates with a 3' unstructured nonanucleotide immediately downstream of the terminal stem-loop (helix 45) of 16S rRNA. This site contains an AUCA sequence highly conserved across all domains of life, immediately upstream of the anti-Shine-Dalgarno sequence, which is conserved in bacteria. Strikingly, this entire region is absent from 12S mt-rRNA. We have mapped the ERAL1-binding site to a 33 nucleotide section delineating the 3' terminal stem-loop region of 12S mt-rRNA. This loop contains two adenine residues that are reported to be dimethylated on mitoribosome maturation. Furthermore, and also in contrast with the bacterial orthologue, loss of ERAL1 leads to rapid decay of nascent 12S mt-rRNA, consistent with a role as a mitochondrial RNA chaperone. Finally, whereas depletion of ERAL1 leads to apoptosis, cell death occurs prior to any appreciable loss of mitochondrial protein synthesis or reduction in the stability of mitochondrial mRNA.

Published
2010
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19. Inhibition of poly(ADP-ribose) polymerase-1 enhances temozolomide and topotecan activity against childhood neuroblastoma.

Author

Daniel RA, Rozanska AL, Thomas HD, Mulligan EA, Drew Y, Castelbuono DJ, Hostomsky Z, Plummer ER, Boddy AV, Tweddle DA, Curtin NJ, and Clifford SC

Subjects
Animals, Cell Line, Tumor, Cell Proliferation drug effects, Dacarbazine pharmacology, Drug Synergism, Humans, Mice, Neuroblastoma pathology, Poly (ADP-Ribose) Polymerase-1, Temozolomide, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Dacarbazine analogs & derivatives, Enzyme Inhibitors pharmacology, Indoles pharmacology, Neuroblastoma drug therapy, Poly(ADP-ribose) Polymerase Inhibitors, Topotecan pharmacology
Abstract

Purpose: High-risk neuroblastoma is characterized by poor survival rates, and the development of improved therapeutic approaches is a priority. Temozolomide and topotecan show promising clinical activity against neuroblastoma. Poly(ADP-ribose) polymerase-1 (PARP-1) promotes DNA repair and cell survival following genotoxic insult; we postulated that its inhibition may enhance the efficacy of these DNA-damaging drugs in pediatric cancers., Experimental Design: We evaluated the chemosensitizing properties of the PARP inhibitor AG014699 (Pfizer, Inc.) in combination with temozolomide and topotecan, against human neuroblastoma cells and xenografts, alongside associated pharmacologic and toxicologic indices., Results: Addition of PARP-inhibitory concentrations of AG014699 significantly potentiated growth inhibition by both topotecan (1.5- to 2.3-fold) and temozolomide (3- to 10-fold) in vitro, with equivalent effects confirmed in clonogenic assays. In two independent in vivo models (NB1691 and SHSY5Y xenografts), temozolomide caused a xenograft growth delay, which was enhanced by co-administration of AG014699, and resulted in complete and sustained tumor regression in the majority (6 of 10; 60%) of cases. Evidence of enhanced growth delay by topotecan/AG014699 co-administration was observed in NB1691 xenografts. AG014699 metabolites distributed rapidly into the plasma (Cmax, 1.2-1.9 nmol/L at 30 min) and accumulated in xenograft tissues (Cmax, 1-2 micromol/L at 120 min), associated with a sustained suppression of PARP-1 enzyme activity. Doses of AG014699 required for potentiation were not toxic per se., Conclusions: These data show enhancement of temozolomide and topotecan efficacy by PARP inhibition in neuroblastoma. Coupled with the acceptable pharmacokinetic, pharmacodynamic, and toxicity profiles of AG014699, our findings provide strong rationale for investigation of PARP inhibitors in pediatric early clinical studies.

Published
2009
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