Protection against doxorubicin-induced cardiomyopathy

  • Description
  • Details
  • Subprojects
  • History
  • Relations
  • Publications
Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-12
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project Description:
Doxorubicin (DOX) is a potent and effective chemotherapeutic agent belonging to the anthracycline class of antibiotics. It is used frequently in the treatment of many hematologic and solid tumor malignancies. Despite its clinical efficacy, DOX's use is often limited by its potential for causing dose-dependent cardiotoxicity. Our recent studies have shown that potent phosphodiesterase-5A (PDE-5A) inhibitor, sildenafil citrate (Viagra), which is known to enhance erectile function in men, induces powerful cardioprotective effect against ischemia-reperfusion injury (I/R) in the rabbit and mouse hearts. The purpose of this application is to show the effect of class of novel PDE-5A inhibitors on DOX-induced cardiomyocyte apoptosis and to understand signaling pathways which leads to a long lasting cardioprotection. We will test the following hypotheses: 1) Suppression ofPDE-5A with novel class of inhibitors attenuate DOX-inducedcardiotoxicity andcontractile dysfunction via inhibition of cardiomyocyte apoptosis in the heart. We will also determine the effect of PDE-5 inhibitors onanti-tumor properties of DOX. 2). PDE-5A inhibitors) trigger signaling mechanismsinvolving activation of transcription factor, GATA-4, which leads to enhanced expression ofBcl-2 and attenuate cardiomyocytes apoptosis following DOX-treatment 3) PDE-5A inhibitors stimulate guanylate cyclase and elevate cGMP causing activationof protein kinase G(PKG)leading to attenuationof DOX-induced cardiotoxicity. 4) PDE-5A inhibitors drive the expression of heat shockproteins through gene transcription andactivation of heat shock transcription factor-1 which mayresult in reduction of DOX-induced cardiotoxicity in the heart. This study will be the first one to demonstrate the protective effect of PDE-5A inhibitors in DOX-induced cardiotoxicity in the heart at cellular and sub-cellular level. These studies will also provide valuable information leading to eventual clinical trials in humans receiving DOX-chemotherapy for hematologic and/or oncologic neoplasms.
 
Project Terms:
(+)-(S)-4,4'-(1-Methyl-1,2-ethanediyl)di(2,6-piperazinedione) (2'-5')oligo(A)-2'-phosphodiesterase (8S-cis)-10-[(3-Amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroacetyl)-1-methoxy-5,12-naphthacenedione 1-(((3-(3,4-dihydro-5-methyl)-4-oxo-7-propylimidazo(5,1-f)-as-triazin-2-yl)-4-ethoxyphenyl)sulfonyl)-4-ethylpiperazine 1-((3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine citrate 1-Phosphatidylinositol 3-Kinase 14-Hydroxydaunomycin 2'-5'-oligoadenylate phosphodiesterase 2'-phosphodiesterase 2,6-Piperazinedione, 4,4'-(1-methyl-1,2-ethanediyl)bis-,(S)-(9CI) 2,6-Piperazinedione, 4,4'propylenedi-,(P)-(8CI) 2-5A phosphodiesterase 5,12-Naphthacenedione, 10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S-cis)- ADP-Ribosyltransferase (Polymerizing) APAETP ATP[{..}]1-phosphatidyl-1D-myo-inositol 3-phosphotransferase Abbott brand of sildenafil citrate Abbreviations Active Oxygen Acute Adenosine Adriamycine Alza Brand of Amifostine Amifostine Aminopropylaminoethylthiophosphoric Acid Anthracycline Antibiotics Anthracyclines Antibiotic Agents Antibiotic Drugs Antibiotics Apoptosis Apoptosis Pathway Apoptotic Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Attenuated BAD BAD gene BBC2 BCL-X/BCL-2 Binding Protein BCL2-Antagonist of Cell Death BCL2-Binding Component 6 BCL2-Binding Protein BCL2-antagonist of cell death protein BCL2L8 Bad protein Bcl-associated death protein Biochemistry Blood Circulation Bloodstream Body Weight decreased Bone Tumor Bone neoplasms Bradykinin Breast Cade Cancer of the Ovary Cancers Cardiac Cardiac Failure Congestive Cardiac Myocytes Cardiac Toxicity Cardiocyte Cardiomyopathies Cardiotoxicity Cardiovascular Diseases Cations Cell Communication and Signaling Cell Death, Programmed Cell Signaling Cessation of Treatment Chemistry, Biological Chemosensitization Chemosensitization/Potentiation Chemotherapy, Cancer, Anthracyclines Chronic Ciclosporin Circulation Class Clinical Clinical Trials Clinical Trials, Unspecified Closure by Ligation Congestive Heart Failure CsA Cultured Cells Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cyclosporin A Cyclosporine Cyclosporine A DNA Binding DNA Binding Interaction DNA Molecular Biology DOX Data Deoxyguanylate Cyclase Development Dexrazoxane Disadvantaged Dose Doxorubicin Doxorubicina Drugs Dysfunction EC 2.7 Enzymes Erectile dysfunction Essex Brand of Amifostine Ethanethiol, 2-((3-aminopropyl)amino)-, dihydrogen phosphate (ester) Ethiofos Ethyol Functional disorder G-Proteins GTP pyrophosphate-lyase (cyclizing) GTP-Binding Proteins GTP-Regulatory Proteins Gammaphos Gastric lymphoma Gene Transcription Gene Transfer Generations Genes Genetic Transcription Guanine Nucleotide Coupling Protein Guanine Nucleotide Regulatory Proteins Guanosine Cyclic 3',5'-Monophosphate Guanosine Cyclic 3',5'-Phosphate-Dependent Protein Kinase Guanosine Cyclic Monophosphate Guanosine Cyclic Monophosphate-Dependent Protein Kinases Guanosine, cyclic 3',5'-(hydrogen phosphate) Guanyl Cyclase Guanylate Cyclase HDL HSP Heart Heart Decompensation Heart Failure, Congestive Heart failure Heart myocyte Heat shock proteins Heating Heavy Lipoproteins High Density Lipoproteins High density lipoprotein Human Human, General Hydroxyl Daunorubicin Hydroxyldaunorubicin In Situ In Vitro Inosinate Cyclase Intracellular Communication and Signaling Investigation Investigators Ischemia-Reperfusion Injury Ischemic Preconditioning Juniperus oxycedrus K element Kaposi - Kaposi's Sarcoma Kaposi Sarcoma Kaposi?s Sarcoma Kinases Lead Ligation Lilly Brand of Amifostine Link Lipoproteins, HDL Lymphoma of the Stomach MMC Malignant Neoplasms Malignant Ovarian Neoplasm Malignant Ovarian Tumor Malignant Tumor Malignant Tumor of the Ovary Malignant neoplasm of ovary Mammals, Mice Mammals, Rabbits Man (Taxonomy) Man, Modern Mediating Mediator Mediator of Activation Mediator of activation protein Medication Membrane Potentials Methods and Techniques Methods, Other Mice Miscellaneous Antibiotic Mitochondria Modeling Molecular Biology Mortality Mortality Vital Statistics Multiple Hemorrhagic Sarcoma Murine Mus Muscle Cells Muscle Cells, Cardiac Muscle Cells, Heart Muscle Cells, Mature Mycocardium Disease Myelosuppression Myocardial Myocardial Diseases Myocardial Disorder Myocardiopathies Myocytes Myocytes, Cardiac NAD+[{..}]poly(adenosine diphosphate D-ribose)-acceptor ADP-D-ribosyltransferase Neoplasms Oligo Oligonucleotides Oryctolagus cuniculus Osseous Neoplasm Osseous Tumor Oxygen Radicals PARP Polymerase PARS PDE PDE4 enzyme PDase IV PI-3 Kinase PI-3K PI3-Kinase PKG Patients Pb element Personal Satisfaction Pfizer brand of sildenafil citrate Pharmaceutic Preparations Pharmaceutical Preparations Phenol, 4,4'-((1-methylethylidene)bis(thio))bis(2,6-bis(1,1-dimethylethyl))- Phosphatidylinositol 3-Kinase Phosphatidylinositol-3-OH Kinase Phosphodiesterases Phosphoinositide 3-Hydroxykinase Phosphorylation Phosphotransferases Physiologic Physiological Physiology Physiopathology Play Poly(ADP-Ribose) Synthase Poly(ADP-Ribose) Transferase Poly(ADP-ribose) Polymerases Poly(ADPR) Polymerase Poly(ADPribose) Polymerase Potassium Potentiation Preconditionings, Ischemic Pro-Oxidants Probucol Programs (PT) Programs [Publication Type] Property Property, LOINC Axis 2 Protein Kinase G Protein Phosphorylation PtdIns 3-Kinase Purpose RNA Expression RNA, Small Interfering Rabbit, Domestic Rabbits Reactive Oxygen Species Receptor Protein Regulation Reperfusion Damage Reperfusion Injury Research Personnel Researchers Resting Potentials Role S-(N-(3-Aminopropyl)-2-aminoethyl)thiophosphoric Acid Sandimmun SangCya Schering-Plough Brand of Amifostine Series Signal Pathway Signal Transduction Signal Transduction Systems Signaling Sildenafil citrate Silenafil Citrate Small Interfering RNA Solid Neoplasm Solid Tumor Soluble ICRF (L-isomer) Stress Stress Proteins Techniques Testing Topoisomerase II inhibition Transcription Transcription, Genetic Transmembrane Potentials Transphosphorylases Tumors Type I Phosphatidylinositol Kinase Type III Phosphoinositide 3-Kinase US Bioscience Brand of Amifostine Viagra Weight Loss Weight Reduction Withholding Treatment alpha-Lipoproteins anthracycline attenuation biological signal transduction body weight loss cGMP cGMP kinase cGMP-Dependent Protein Kinases cardiac failure cardiomyocyte cardiovascular disorder chemotherapeutic agent chemotherapy clinical efficacy clinical investigation clinical relevance clinically relevant cyclosporin A-SPTP cyclosporin A-sensitive pereability transition pore drug/agent guanosine 3'5'monophosphate guanylyl cyclase heat shock transcription factor heavy metal Pb heavy metal lead in vivo in vivo Model indexing inhibitor inhibitor/antagonist insight kallidin 9 kallidin I malignancy men men's mitoK(ATP) mitoKATP mitochondrial mitochondrial K(ATP) channel mitochondrial megachannel mitochondrial membrane mitochondrial permeability transition pore mouse model myocardium disorder neoplasia neoplasm/cancer neoplastic neoplastic growth neoral novel ovarian cancer pathophysiology phosphodiesterase 4 phosphodiesterase IV phosphoric diester hydrolase poly ADP polymerase poly ADP ribose synthetase preconditioning prevent preventing programs protective effect receptor sandimmune siRNA sildenafil social role tadalafil transcription factor transfer of a gene tumor type 4 cyclic nucleotide phosphodiesterase vardenafil well-being wt-loss
Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-12
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project Categories:
• Natural Sciences > Aging Diseases and Pathology > Cardiovascular and cerebrovascular diseases, Cancer & related diseases > Cardiomyopathy, Malignant neoplasms (including in situ) > Head and Neck Cancer
 
Other Information:
Fiscal Year: 1995
Project Start Date: 1 August 1995
Project End Date: 31 December 2010
Administering Institute Or Center: HL
 
Project Funding Information:
Total Funding: $357,248
Year Funding Organization Total Funding, $
2008 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE $357,248
Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-12
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-12
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project number Project title Organization FY Funding Organization FY Total Cost
5R01HL059469-07Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2004NATIONAL HEART
$375,000
5R01HL051045-09SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2004NATIONAL HEART
$290,000
5R01HL059469-06Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2003NATIONAL HEART
$375,000
5R01HL051045-08SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2003NATIONAL HEART
$290,000
2R01HL059469-05Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2002NATIONAL HEART
$375,000
5R01HL051045-07SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2002NATIONAL HEART
$290,000
5R01HL059469-04MOLECULAR MECHANISMS OF DELAYED PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2001NATIONAL HEART
$265,698
5R01HL051045-06SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2001NATIONAL HEART
$290,000
5R01HL059469-03MOLECULAR MECHANISMS OF DELAYED PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2000NATIONAL HEART
$258,001
2R01HL051045-05SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2000NATIONAL HEART
$281,900
5R01HL059469-08Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2005NATIONAL HEART
$375,000
1R01HL079424-01CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2005NATIONAL HEART
$454,713
5R01HL059469-09Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2006NATIONAL HEART
$366,188
5R01HL079424-02CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2006NATIONAL HEART
$440,694
2R37HL051045-10Protection against Doxorubicin-Induced CardiomyopathyVIRGINIA COMMONWEALTH UNIVERSITY2006NATIONAL HEART
$365,640
5R01HL079424-03CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2007NATIONAL HEART
$450,503
5R37HL051045-11Protection against Doxorubicin-Induced CardiomyopathyVIRGINIA COMMONWEALTH UNIVERSITY2007NATIONAL HEART
$361,698
5R01HL079424-04CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2008NATIONAL HEART
$454,221
1R01HL093685-01Cardioprotective Signaling following Phosphodiesterase-5 InhibitionVIRGINIA COMMONWEALTH UNIVERSITY2008NATIONAL HEART
$372,500
1R25HL092622-01Health Educational Research Opportunities (HERO)VIRGINIA COMMONWEALTH UNIVERSITY2008NATIONAL HEART
$93,118
Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-12
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project number Project title Principal investigator
There are no any related projects.
Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-12
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Title Abstract Authors Year Rel
Hypoxia inducible factor-1 upregulates adiponectin in diabetic mouse hearts and attenuates post-ischemic injury. Journal of cardiovascular pharmacology. 2008 Feb 51 (2) :178-87 Natarajan, Ramesh; Salloum, Fadi N; Fisher, Bernard J; Kukreja, Rakesh C; Fowler 3rd, Alpha A 2008
Loss of myocardial ischemic postconditioning in adenosine A1 and bradykinin B2 receptors gene knockout mice. Circulation. 2008 Sep 30 118 (14 Suppl) :S32-7 Xi, Lei; Das, Anindita; Zhao, Zhi-Qing; Merino, Vanessa F; Bader, Michael; Kukreja, Rakesh C 2008
Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice. American journal of physiology. Heart and circulatory physiology. 2008 Mar 294 (3) :H1398-406 Salloum, Fadi N; Abbate, Antonio; Das, Anindita; Houser, Jon-Erik; Mudrick, Colin A; Qureshi, Ian Z; Hoke, Nicholas N; Roy, Sion K; Brown, William R; Prabhakar, Shashi; Kukreja, Rakesh C 2008
Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation. 2008 May 20 117 (20) :2670-83 Abbate, Antonio; Salloum, Fadi N; Vecile, Elena; Das, Anindita; Hoke, Nicholas N; Straino, Stefania; Biondi-Zoccai, Giuseppe G L; Houser, Jon-Erik; Qureshi, Ian Z; Ownby, Evan D; Gustini, Edoardo; Biasucci, Luigi M; Severino, Anna; Capogrossi, Maurizio C; Vetrovec, George W; Crea, Filippo; Baldi, Alfonso; Kukreja, Rakesh C; Dobrina, Aldo 2008
Essential role of mitochondrial Ca2+-activated and ATP-sensitive K+ channels in sildenafil-induced late cardioprotection. Journal of molecular and cellular cardiology. 2008 Jan 44 (1) :105-13 Wang, Xiaoyin; Fisher, Patrick W; Xi, Lei; Kukreja, Rakesh C 2008
Endogenous microRNAs induced by heat-shock reduce myocardial infarction following ischemia-reperfusion in mice. FEBS letters. 2008 Dec 24 582 (30) :4137-42 Yin, Chang; Wang, Xiaoyin; Kukreja, Rakesh C 2008
Right ventricular cardiomyocyte apoptosis in patients with acute myocardial infarction of the left ventricular wall. The American journal of cardiology. 2008 Sep 15 102 (6) :658-62 Abbate, Antonio; Bussani, Rossana; Sinagra, Gianfranco; Barresi, Elena; Pivetta, Alberto; Perkan, Andrea; Hoke, Nicholas H; Salloum, Fadi N; Kontos, Michael C; Biondi-Zoccai, Giuseppe G L; Vetrovec, George W; Sabbadini, Gastone; Baldi, Feliciano; Silvestri, Furio; Kukreja, Rakesh C; Baldi, Alfonso 2008
Protein kinase G-dependent cardioprotective mechanism of phosphodiesterase-5 inhibition involves phosphorylation of ERK and GSK3beta. The Journal of biological chemistry. 2008 Oct 24 283 (43) :29572-85 Das, Anindita; Xi, Lei; Kukreja, Rakesh C 2008