DOCSLIB.ORG

Anagrelide for Gastrointestinal Stromal Tumor

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Anagrelide for Gastrointestinal Stromal Tumor Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Anagrelide for gastrointestinal stromal tumor Olli-Pekka Pulkka1, Yemarshet K. Gebreyohannes2, Agnieszka Wozniak2, John-Patrick Mpindi3, Olli Tynninen4, Katherine Icay5, Alejandra Cervera5, Salla Keskitalo6, Astrid Murumägi3, Evgeny Kulesskiy3, Maria Laaksonen7, Krister Wennerberg3, Markku Varjosalo6, Pirjo Laakkonen8, Rainer Lehtonen5, Sampsa Hautaniemi5, Olli Kallioniemi3, Patrick Schöffski2, Harri Sihto1*, and Heikki Joensuu1,9* 1Laboratory of Molecular Oncology, Research Programs Unit, Translational Cancer Biology, Department of Oncology, University of Helsinki, Helsinki, Finland. 2Laboratory of Experimental Oncology, Department of Oncology, KU Leuven and Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. 3Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland 4Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki, Finland. 5Research Programs Unit, Genome-Scale Biology, Medicum and Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. 6Institute of Biotechnology, University of Helsinki, Helsinki, Finland. 7MediSapiens Ltd., Helsinki, Finland 8Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland. 9Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 *Shared authorship Running title: Anagrelide for GIST Keywords: Gastrointestinal stromal tumor, Phosphodiesterase 3, Anagrelide, Imatinib Financial Support: This study was supported by the Academy of Finland, Center of Excellence for Translational Cancer Biology, Cancer Society of Finland, Jane and Aatos Erkko Foundation, HUCH Research Funds, Sigrid Juselius Foundation, Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society (Belgium), Ida Montin Foundation, Emil Aaltonen Foundation, and Luise and Henrik Kuningas Foundation. Disclosure of Potential Conflicts of Interest: O.P. Pulkka, O. Kallioniemi, H. Sihto, and H. Joensuu own stocks of Sartar Therapeutics and are board members. H. Joensuu has a co- appointment at Orion Pharma, and has received fees from Orion Pharma and Neutron Therapeutics Ltd. Other authors declare no conflict of interest. Corresponding Author: Heikki Joensuu, MD, Comprehensive Cancer Center, Helsinki University Hospital, Haartmaninkatu 4, PO Box 180, FIN-00029 Helsinki, Finland; fax: (+358) 9 471 74202; Phone: (+358) 40 72 10438; e-mail: [email protected]. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 3 Translational Relevance GISTs frequently harbor either mutated KIT or PDGFRA that encode a constitutively activated receptor tyrosine kinase. Imatinib, an inhibitor of KIT, PDGFRA, and a few other kinases, revolutionized the systemic treatment of GIST, but second mutations that inhibit imatinib and other tyrosine kinase inhibitors from binding to the activated kinases often eventually emerge leading to GIST progression. Enzymes of the phosphodiesterase 3 family (PDE3A and PDE3B) are highly expressed in GIST compared to many other types of human cancer, which may open an opportunity for an efficient targeted therapy. Anagrelide, a PDE3- specific modulator marketed for the treatment of thrombocytemia, decreases GIST cell proliferation, and promotes their apoptosis in vitro. Anagrelide inhibited GIST growth in patient-derived mouse xenograft models. Anagrelide may have therapeutic value in the treatment of GIST. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 4 Abstract Purpose: Gastrointestinal stromal tumor (GIST) is a common type of soft tissue sarcoma. Imatinib, an inhibitor of KIT, PDFGRA and a few other tyrosine kinases, is highly effective for GIST, but advanced GISTs frequently progress on imatinib and other approved tyrosine kinase inhibitors. We investigated phosphodiesterase 3 (PDE3) as a potential therapeutic target in GIST cell lines and xenograft models. Experimental Design: The GIST gene expression profile was interrogated in the MediSapiens IST Online transcriptome database comprising of human tissue and cancer samples, and PDE3A and PDE3B expression was studied using immunohistochemistry on tissue microarrays (TMAs) consisting of 630 formalin-fixed human tissue samples. GIST cell lines were screened for sensitivity to 217 anti-cancer compounds, and the efficacy of PDE inhibitors on GIST was further studied in GIST cell lines and patient-derived mouse xenograft models. Results: GISTs expressed PDE3A and PDE3B frequently compared to other human normal or cancerous tissues both in the in silico database and the TMAs. Anagrelide was identified as the most potent of the PDE3 modulators evaluated. It reduced cell viability, promoted cell death, and influenced cell signaling in GIST cell lines. Anagrelide inhibited tumor growth in GIST xenograft mouse models. Anagrelide was effective also in a GIST xenograft mouse model with KIT exon 9 mutation that may pose a therapeutic challenge, as these GISTs require a high daily dose of imatinib. Conclusions: PDE3A and PDE3B are frequently expressed in GIST. Anagrelide had anti- cancer efficacy in GIST xenograft models, and warrants further testing in clinical trials. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 5 Introduction Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma that arises from the gastrointestinal tract. GISTs frequently harbor aberrant KIT or platelet derived growth factor receptor alpha (PDGFRA) that encode constitutively activated receptor tyrosine kinases (1, 2), but a minority of GISTs lack a mutation in these genes (3). Most GIST patients with a KIT mutation or a PDGFRA mutation can be effectively treated with tyrosine kinase inhibitors such as imatinib or other agents (4), but second mutations conferring drug resistance emerge frequently leading to GIST progression (5). Sunitinib and regorafenib, the approved second-line and third-line agents for advanced GIST, are effective, but the median time to disease progression was 6 months or less with these agents in the pivotal randomized trials (6, 7). Therefore, there is a need for novel effective agents for the treatment of patients with advanced GIST. Phosphodiesterase (PDE) 3A and 3B are cyclic nucleotide phosphodiesterases that regulate the intracellular concentration, localization, and signaling of cyclic AMP (cAMP), and/or cyclic GMP (cGMP) by controlling their degradation (8). cAMP and cGMP signaling regulate various physiological processes, including cell proliferation and differentiation, inflammation, gene expression, apoptosis, and metabolic pathways (9-11). PDE3A is expressed in the smooth muscle, platelets, and cardiac tissues, and it is involved in platelet aggregation and in the regulation of the blood pressure, cardiac function, and oocyte meiosis (8, 12). PDE3B is frequently expressed in cells that are important in energy homeostasis, such as adipocytes and hepatocytes (8). PDE3B is important especially in insulin signaling (13). Some types of cancer, such as chronic lymphocytic leukemia (CLL) and colorectal cancer, express low levels of cAMP as a consequence of overexpression of PDEs (14, 15), and inhibition of various PDEs has antitumor effects in several cancer cell lines (16). High Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 6 PDE3A expression is associated with Sclaffen12 (SLFN12) expression in GIST (17, 18). In one study, the PDE3 inhibitor cilostazol reduced the GIST882 cell line viability, and the PDE3A SLFN12 interaction was suggested to have a role in cell death (17). Anagrelide hydrochloride targets the PDE3 enzyme family and reduces the peripheral blood platelet numbers by inhibiting megakaryopoiesis in the bone marrow (19, 20), and is used for the treatment of essential thrombocythemia (21, 22). Anagrelide inhibits the cyclic AMP phosphodiesterase activity elevating the cAMP levels in platelets (23, 24) In the present study we investigated the role of PDE3 in
Load more

Recommended publications
  • Theophylline and Selective PDE Inhibitors As Bronchodilators and Smooth Muscle Relaxants
    Eur Respir J, 1995, 8, 637–642 Copyright ERS Journals Ltd 1995 DOI: 10.1183/09031936.95.08040637 European Respiratory Journal Printed in UK - all rights reserved ISSN 0903 - 1936 SERIES 'THEOPHYLLINE AND PHOSPHODIESTERASE INHIBITORS' Edited by M. Aubier and P.J. Barnes Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants K.F. Rabe, H. Magnussen, G. Dent Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. Krankenhaus Grosshansdorf, Zentrum für K.F. Rabe, H. Magnussen, G. Dent. ERS Journals Ltd 1995. Pneumologie und Thoraxchirurgie, LVA ABSTRACT: In addition to its emerging immunomodulatory properties, theophy- Hamburg, Grosshansdorf, Germany. lline is a bronchodilator and also decreases mean pulmonary arterial pressure in vivo. The mechanism of action of this drug remains controversial; adenosine Correspondence: K.F. Rabe Krankenhaus Grosshansdorf antagonism, phosphodiesterase (PDE) inhibition and other actions have been advanced Wöhrendamm 80 to explain its effectiveness in asthma. Cyclic adenosine monophosphate (AMP) and D-22927 Grosshansdorf cyclic guanosine monophosphate (GMP) are involved in the regulation of smooth Germany muscle tone, and the breakdown of these nucleotides is catalysed by multiple PDE isoenzymes. The PDE isoenzymes present in human bronchus and pulmonary artery Keywords: Bronchi have been identified, and the pharmacological actions of inhibitors of these enzy- 3',5'-cyclic-nucleotide phosphodiesterase mes have been investigated. phosphodiesterase inhibitors Human bronchus and pulmonary arteries are relaxed by theophylline and by pulmonary artery selective inhibitors of PDE III, while PDE IV inhibitors also relax precontracted smooth muscle theophylline bronchus and PDE V/I inhibitors relax pulmonary artery. There appears to be some synergy between inhibitors of PDE III and PDE IV in relaxing bronchus, and Received: February 1 1995 a pronounced synergy between PDE III and PDE V inhibitors in relaxing pulmon- Accepted for publication February 1 1995 ary artery.
    [Show full text]
  • PDE4-Inhibitors: a Novel, Targeted Therapy for Obstructive Airways Disease Zuzana Diamant, Domenico Spina
    PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease Zuzana Diamant, Domenico Spina To cite this version: Zuzana Diamant, Domenico Spina. PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease. Pulmonary Pharmacology & Therapeutics, 2011, 24 (4), pp.353. 10.1016/j.pupt.2010.12.011. hal-00753954 HAL Id: hal-00753954 https://hal.archives-ouvertes.fr/hal-00753954 Submitted on 20 Nov 2012 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Accepted Manuscript Title: PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease Authors: Zuzana Diamant, Domenico Spina PII: S1094-5539(11)00006-X DOI: 10.1016/j.pupt.2010.12.011 Reference: YPUPT 1071 To appear in: Pulmonary Pharmacology & Therapeutics Received Date: 2 October 2010 Revised Date: 5 December 2010 Accepted Date: 24 December 2010 Please cite this article as: Diamant Z, Spina D. PDE4-inhibitors: A novel, targeted therapy for obstructive airways disease, Pulmonary Pharmacology & Therapeutics (2011), doi: 10.1016/j.pupt.2010.12.011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.
    [Show full text]
  • Drug Name Plate Number Well Location % Inhibition, Screen Axitinib 1 1 20 Gefitinib (ZD1839) 1 2 70 Sorafenib Tosylate 1 3 21 Cr
    Drug Name Plate Number Well Location % Inhibition, Screen Axitinib 1 1 20 Gefitinib (ZD1839) 1 2 70 Sorafenib Tosylate 1 3 21 Crizotinib (PF-02341066) 1 4 55 Docetaxel 1 5 98 Anastrozole 1 6 25 Cladribine 1 7 23 Methotrexate 1 8 -187 Letrozole 1 9 65 Entecavir Hydrate 1 10 48 Roxadustat (FG-4592) 1 11 19 Imatinib Mesylate (STI571) 1 12 0 Sunitinib Malate 1 13 34 Vismodegib (GDC-0449) 1 14 64 Paclitaxel 1 15 89 Aprepitant 1 16 94 Decitabine 1 17 -79 Bendamustine HCl 1 18 19 Temozolomide 1 19 -111 Nepafenac 1 20 24 Nintedanib (BIBF 1120) 1 21 -43 Lapatinib (GW-572016) Ditosylate 1 22 88 Temsirolimus (CCI-779, NSC 683864) 1 23 96 Belinostat (PXD101) 1 24 46 Capecitabine 1 25 19 Bicalutamide 1 26 83 Dutasteride 1 27 68 Epirubicin HCl 1 28 -59 Tamoxifen 1 29 30 Rufinamide 1 30 96 Afatinib (BIBW2992) 1 31 -54 Lenalidomide (CC-5013) 1 32 19 Vorinostat (SAHA, MK0683) 1 33 38 Rucaparib (AG-014699,PF-01367338) phosphate1 34 14 Lenvatinib (E7080) 1 35 80 Fulvestrant 1 36 76 Melatonin 1 37 15 Etoposide 1 38 -69 Vincristine sulfate 1 39 61 Posaconazole 1 40 97 Bortezomib (PS-341) 1 41 71 Panobinostat (LBH589) 1 42 41 Entinostat (MS-275) 1 43 26 Cabozantinib (XL184, BMS-907351) 1 44 79 Valproic acid sodium salt (Sodium valproate) 1 45 7 Raltitrexed 1 46 39 Bisoprolol fumarate 1 47 -23 Raloxifene HCl 1 48 97 Agomelatine 1 49 35 Prasugrel 1 50 -24 Bosutinib (SKI-606) 1 51 85 Nilotinib (AMN-107) 1 52 99 Enzastaurin (LY317615) 1 53 -12 Everolimus (RAD001) 1 54 94 Regorafenib (BAY 73-4506) 1 55 24 Thalidomide 1 56 40 Tivozanib (AV-951) 1 57 86 Fludarabine
    [Show full text]
  • Phosphodiesterase (PDE)
    Phosphodiesterase (PDE) Phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases. The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators ofsignal transduction mediated by these second messenger molecules. www.MedChemExpress.com 1 Phosphodiesterase (PDE) Inhibitors, Activators & Modulators (+)-Medioresinol Di-O-β-D-glucopyranoside (R)-(-)-Rolipram Cat. No.: HY-N8209 ((R)-Rolipram; (-)-Rolipram) Cat. No.: HY-16900A (+)-Medioresinol Di-O-β-D-glucopyranoside is a (R)-(-)-Rolipram is the R-enantiomer of Rolipram. lignan glucoside with strong inhibitory activity Rolipram is a selective inhibitor of of 3', 5'-cyclic monophosphate (cyclic AMP) phosphodiesterases PDE4 with IC50 of 3 nM, 130 nM phosphodiesterase. and 240 nM for PDE4A, PDE4B, and PDE4D, respectively. Purity: >98% Purity: 99.91% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 10 mM × 1 mL, 10 mg, 50 mg (R)-DNMDP (S)-(+)-Rolipram Cat. No.: HY-122751 ((+)-Rolipram; (S)-Rolipram) Cat. No.: HY-B0392 (R)-DNMDP is a potent and selective cancer cell (S)-(+)-Rolipram ((+)-Rolipram) is a cyclic cytotoxic agent. (R)-DNMDP, the R-form of DNMDP, AMP(cAMP)-specific phosphodiesterase (PDE) binds PDE3A directly.
    [Show full text]
  • Pharmaceutical Appendix to the Harmonized Tariff Schedule
    Harmonized Tariff Schedule of the United States (2019) Revision 13 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2019) Revision 13 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • Rolipram, but Not Siguazodan Or Zaprinast, Inhibits the Excitatory Noncholinergic Neurotransmission in Guinea-Pig Bronchi
    Eur Respir J, 1994, 7, 306–310 Copyright ERS Journals Ltd 1994 DOI: 10.1183/09031936.94.07020306 European Respiratory Journal Printed in UK - all rights reserved ISSN 0903 - 1936 Rolipram, but not siguazodan or zaprinast, inhibits the excitatory noncholinergic neurotransmission in guinea-pig bronchi Y. Qian, V. Girard, C.A.E. Martin, M. Molimard, C. Advenier Rolipram, but not siguazodan or zaprinast, inhibits the excitatory noncholinergic neuro- Faculté de Médecine Paris-Ouest Labora- transmission in guinea-pig bronchi. Y. Qian, V. Girard C.A.E. Martin, M. Molimard, toire de Pharmacologie, Paris, France. C. Advenier. ERS Journals Ltd 1994. ABSTRACT: Theophylline has been reported to inhibit excitatory noncholinergic Correspondence: C. Advenier Faculté de Médecine Paris-Ouest but not cholinergic-neurotransmission in guinea-pig bronchi. As theophylline might Laboratoire de Pharmacologie exert this effect through an inhibition of phosphodiesterases (PDE), and since many 15, Rue de l'Ecole de Médecine types of PDE have now been described, the aim of this study was to investigate the F-75270 Paris Cedex 06 effects of three specific inhibitors of PDE on the electrical field stimulation (EFS) France of the guinea-pig isolated main bronchus in vitro. The drugs used were siguazo- dan, rolipram and zaprinast, which specifically inhibit PDE types, III, IV and V, Keywords: C-fibres respectively. neuropeptides Guinea-pig bronchi were stimulated transmurally with biphasic pulses (16 Hz, 1 phosphodiesterase inhibitors ms, 320 mA for 10 s) in the presence of indomethacin 10-6 M and propranolol 10-6 Received: March 11 1993 M. Two successive contractile responses were observed: a rapid cholinergic con- Accepted after revision August 8 1993 traction, followed by a long-lasting contraction due to a local release of neuropep- tides from C-fibre endings.
    [Show full text]
  • Integrated Technologies for the Characterization Of
    Integrated technologies for the characterization of phosphodiesterase (PDE) inhibitors Edmond Massuda, Lisa Fleet, Benjamin Lineberry, Laurel Provencher, Abbie Esterman, Dhanrajan Tiruchinapalli, Faith Gawthrop, Christopher Spence, Rajneesh P. Uzgare, Scott Perschke, Seth Cohen, and Hao Chen. 618.01/XX63 Caliper Life Sciences, a PerkinElmer Company, 7170 Standard Drive, Hanover, Maryland, 21076 USA Abstract Phosphodiesterases (PDEs) are a class of signal transduction enzymes regulating various cellular functions and disease Results Results progressions in a number of central or peripheral nervous system-related disorders. For example, these enzymes are involved in neurological diseases including psychosis in schizophrenia, multiple sclerosis and other neurodegenerative PDE1A PDE1B PDE2A PDE3A PDE3B PDE4A1A PDE4B1 Ki and kinact determination using 3D Fit Model 110 110 110 110 110 100 110 110 100 100 100 Percent of Maximum Activity by Time 100 conditions. Thus, safe and highly selective PDE inhibitors or modulators are becoming an important class of disease 100 90 100 90 90 90 90 90 80 90 80 80 80 80 modifying therapeutic agents. We have developed an integrated platform which includes Caliper LabChip™ microfluidic 80 70 80 70 70 70 70 70 60 70 60 60 60 60 mobility-shift assays measuring fluorescent analogs of cAMP and cGMP in conjunction with a cellular assay 60 60 50 50 50 50 50 50 50 40 40 40 40 characterizing intracellular signal transduction in cells modulated by PDE inhibitors. These technologies are useful in 40 40 40 30 30 30 30 %%
    [Show full text]
  • Three-Dimensional Structures of PDE4D in Complex with Roliprams and Implication on Inhibitor Selectivity
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Structure, Vol. 11, 865–873, July, 2003, 2003 Elsevier Science Ltd. All rights reserved. DOI 10.1016/S0969-2126(03)00123-0 Three-Dimensional Structures of PDE4D in Complex with Roliprams and Implication on Inhibitor Selectivity Qing Huai, Huanchen Wang, Yingjie Sun, 7, and 8 prefer to hydrolyze cAMP, while PDE5, 6, and Hwa-Young Kim, Yudong Liu, and Hengming Ke* 9 are cGMP specific. PDE1, 2, 3, 10, and 11 take both Department of Biochemistry and Biophysics and cAMP and cGMP as their substrates. In the past three Lineberger Comprehensive Cancer Center decades, selective inhibitors against the different PDE The University of North Carolina, Chapel Hill families have been widely studied as cardiotonic agents, Chapel Hill, North Carolina 27599 vasodilators, smooth muscle relaxants, antidepres- sants, antithrombotic compounds, antiasthma com- pounds, and agents for improving cognitive functions Summary such as memory (Reilly and Mohler, 2001; Rotella, 2002; Giembycz, 2000; Souness et al., 2000; Huang et al., Selective inhibitors against the 11 families of cyclic 2001). For example, the PDE5 inhibitor sildenafil (Viagra; nucleotide phosphodiesterases (PDEs) are used to Figure 1) is a drug for male erectile dysfunction, and the treat various human diseases. How the inhibitors se- PDE3 inhibitor cilostamide is a drug for heart diseases. lectively bind the conserved PDE catalytic domains is Selective inhibitors of PDE4 form the largest group of unknown. The crystal structures of the PDE4D2 cata- inhibitors for any PDE family and have been studied as lytic domain in complex with (R)- or (R,S)-rolipram sug- anti-inflammatory drugs targeting asthma and chronic gest that inhibitor selectivity is determined by the obstructive pulmonary disease (COPD) and also as ther- chemical nature of amino acids and subtle conforma- apeutic agents for rheumatoid arthritis, multiple sclero- tional changes of the binding pockets.
    [Show full text]
  • 68 Suppl. 2: 3-57 REVIEW ARTICLE 0012-6667/08/0002-0003/$53.45/0
    Drugs 2008; 68 Suppl. 2: 3-57 REVIEW ARTICLE 0012-6667/08/0002-0003/$53.45/0 © 2008 Adis Data Information BV. All rights reserved. The Efficacy and Safety of Cilomilast in COPD Stephen Rennard,1 Katharine Knobil,2 Klaus F. Rabe,3 Andrea Morris,2 Neil Schachter,4 Nicholas Locantore,2 Walter G. Canonica,5 Yuanjue Zhu6 and Frank Barnhart2 1 Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA 2 GlaxoSmithKline, Research Triangle Park, North Carolina, USA 3 Leiden University Medical Centre, Leiden, the Netherlands 4 Mount Sinai School of Medicine, New York City, New York, USA 5 Medical University of Genoa, Genoa, Italy 6 Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China Contents Abstract ..................................................................................... 5 1. Introduction .............................................................................. 6 1.1 Chronic Obstructive Pulmonary Disease (COPD) ......................................... 6 1.2 Potential Shortcomings of Pharmacotherapy in COPD .................................... 6 1.3 Phosphodiesterase Inhibitors ........................................................... 7 1.4 Clinical Studies with Cilomilast .......................................................... 8 2. Evidence of Anti-Inflammatory Activity of Cilomilast in Induced Sputum and Bronchial Biopsies from COPD Patients ....................................................................... 8 2.1 Study Objectives .....................................................................
    [Show full text]
  • Phosphodiesterase Inhibitors: Could They Be Beneficial for the Treatment of COVID-19?
    International Journal of Molecular Sciences Review Phosphodiesterase Inhibitors: Could They Be Beneficial for the Treatment of COVID-19? Mauro Giorgi 1,*, Silvia Cardarelli 2, Federica Ragusa 3, Michele Saliola 1, Stefano Biagioni 1, Giancarlo Poiana 1 , Fabio Naro 2 and Mara Massimi 3,* 1 Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy; [email protected] (M.S.); [email protected] (S.B.); [email protected] (G.P.) 2 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University, 00185 Rome, Italy; [email protected] (S.C.); [email protected] (F.N.) 3 Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; [email protected] * Correspondence: [email protected] (M.G.); [email protected] (M.M.) Received: 10 July 2020; Accepted: 24 July 2020; Published: 27 July 2020 Abstract: In March 2020, the World Health Organization declared the severe acute respiratory syndrome corona virus 2 (SARS-CoV2) infection to be a pandemic disease. SARS-CoV2 was first identified in China and, despite the restrictive measures adopted, the epidemic has spread globally, becoming a pandemic in a very short time. Though there is growing knowledge of the SARS-CoV2 infection and its clinical manifestations, an effective cure to limit its acute symptoms and its severe complications has not yet been found. Given the worldwide health and economic emergency issues accompanying this pandemic, there is an absolute urgency to identify effective treatments and reduce the post infection outcomes. In this context, phosphodiesterases (PDEs), evolutionarily conserved cyclic nucleotide (cAMP/cGMP) hydrolyzing enzymes, could emerge as new potential targets.
    [Show full text]
  • Various Subtypes of Phosphodiesterase Inhibitors Differentially Regulate Pulmonary Vein and Sinoatrial Node Electrical Activities
    EXPERIMENTAL AND THERAPEUTIC MEDICINE 19: 2773-2782, 2020 Various subtypes of phosphodiesterase inhibitors differentially regulate pulmonary vein and sinoatrial node electrical activities YUNG‑KUO LIN1,2*, CHEN‑CHUAN CHENG3*, JEN‑HUNG HUANG1,2, YI-ANN CHEN4, YEN-YU LU5, YAO‑CHANG CHEN6, SHIH‑ANN CHEN7 and YI-JEN CHEN1,8 1Department of Internal Medicine, Division of Cardiovascular Medicine, Wan Fang Hospital; 2Department of Internal Medicine, Division of Cardiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11696; 3Division of Cardiology, Chi‑Mei Medical Center, Tainan 71004; 4Division of Nephrology; 5Division of Cardiology, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei 22174; 6Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490; 7Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217; 8Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11696, Taiwan, R.O.C. Received May 16, 2019; Accepted January 9, 2020 DOI: 10.3892/etm.2020.8495 Abstract. Phosphodiesterase (PDE)3-5 are expressed in 20.7±4.6%, respectively. In addition, milrinone (1 and 10 µM) cardiac tissue and play critical roles in the pathogenesis of induced the occurrence of triggered activity (0/8 vs. 5/8; heart failure and atrial fibrillation. PDE inhibitors are widely P<0.005) in PVs. Rolipram increased PV spontaneous activity used in the clinic, but their effects on the electrical activity by 7.5±1.3‑9.5±4.0%, although this was not significant, and did of the heart are not well understood. The aim of the present not alter SAN spontaneous activity.
    [Show full text]
  • Selective PDE4 Inhibitors As Potent Anti-Inflammatory Drugs for The
    Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 100(Suppl. I): 131-136, 2005 131 Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases Vincent Lagente/+, Corinne Martin-Chouly, Elisabeth Boichot, Marco A Martins*, Patrica MR Silva* INSERM U620, Faculté de Pharmacie, Université de Rennes 1, 2, avenue du Professeur Léon Bernard, 35043, Rennes Cedex, Rennes, France *Laboratório de Inflamação, Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz-Fiocruz, Rio de Janeiro, RJ, Brasil Phosphodiesterases (PDEs) are responsible for the breakdown of intracellular cyclic nucleotides, from which PDE4 are the major cyclic AMP metabolizing isoenzymes found in inflammatory and immune cells. This generated greatest interest on PDE4 as a potential target to treat lung inflammatory diseases. For example, cigarette smoke- induced neutrophilia in BAL was dose and time dependently reduced by cilomilast. Beside the undesired side effects associated with the first generation of PDE4 inhibitors, the second generation of selective inhibitors such as cilomilast and roflumilast showed clinical efficacy in asthma and chronic obstrutive pulmonary diseases trials, thus re-enhancing the interest on these classes of compounds. However, the ability of PDE4 inhibitors to prevent or modulate the airway remodelling remains relatively unexplored. We demonstrated that selective PDE4 inhibitor RP 73-401 reduced matrix metalloproteinase (MMP)-9 activity and TGF-β1 release during LPS-induced lung injury in mice and that CI-1044 inhibited the production of MMP-1 and MMP-2 from human lung fibroblasts stimulated by pro-inflammatory cytokines. Since inflammatory diseases of the bronchial airways are associated with destruction of normal tissue structure, our data suggest a therapeutic benefit for PDE4 inhibitors in tissue remodelling associated with chronic lung diseases.
    [Show full text]