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 lead to a long lasting cardioprotection. We will test the following hypotheses: 1) Suppression of PDE-5A with novel class of inhibitors attenuate DOX-induced cardiotoxicity and contractile dysfunction via inhibition of cardiomyocyte apoptosis in the heart. We will also determine the effect of PDE-5 inhibitors on anti-tumor properties of DOX. 2). PDE-5A inhibitor(s) trigger signaling mechanisms involving activation of transcription factor, GATA-4, which leads to enhanced expression of Bcl-2 and attenuate cardiomyocytes apoptosis following DOX-treatment 3) PDE-5A inhibitors stimulate guanylate cyclase and elevate cGMP causing activation of protein kinase G (PKG) leading to attenuation of DOX-induced cardiotoxicity. 4) PDE-5A inhibitors drive the expression of heat shock proteins through gene transcription and activation of heat shock transcription factor-1 which may result 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL051045-11
Application #
7162971
Study Section
Special Emphasis Panel (ZRG1-CVS-B (03))
Program Officer
Liang, Isabella Y
Project Start
1995-08-01
Project End
2010-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
11
Fiscal Year
2007
Total Cost
$361,698
Indirect Cost
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Wang, Rui; Xi, Lei; Kukreja, Rakesh C (2017) PDE5 Inhibitor Tadalafil and Hydroxychloroquine Cotreatment Provides Synergistic Protection against Type 2 Diabetes and Myocardial Infarction in Mice. J Pharmacol Exp Ther 361:29-38
Kuriakose, Robin K; Kukreja, Rakesh C; Xi, Lei (2016) Potential Therapeutic Strategies for Hypertension-Exacerbated Cardiotoxicity of Anticancer Drugs. Oxid Med Cell Longev 2016:8139861
Das, Anindita; Durrant, David; Mitchell, Clint et al. (2016) Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95. Oncotarget 7:4399-413
Gill, Rabia; Kuriakose, Robin; Gertz, Zachary M et al. (2015) Remote ischemic preconditioning for myocardial protection: update on mechanisms and clinical relevance. Mol Cell Biochem 402:41-9
Das, Anindita; Samidurai, Arun; Hoke, Nicholas N et al. (2015) Hydrogen sulfide mediates the cardioprotective effects of gene therapy with PKG-I?. Basic Res Cardiol 110:42
Das, Anindita; Durrant, David; Salloum, Fadi N et al. (2015) PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer. Pharmacol Ther 147:12-21
Salloum, Fadi N; Sturz, Gregory R; Yin, Chang et al. (2015) Beetroot juice reduces infarct size and improves cardiac function following ischemia-reperfusion injury: Possible involvement of endogenous H2S. Exp Biol Med (Maywood) 240:669-81
Das, Anindita; Salloum, Fadi N; Filippone, Scott M et al. (2015) Inhibition of mammalian target of rapamycin protects against reperfusion injury in diabetic heart through STAT3 signaling. Basic Res Cardiol 110:31
Durrant, David E; Das, Anindita; Dyer, Samya et al. (2015) Targeted Inhibition of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Sensitizes Pancreatic Cancer Cells to Doxorubicin without Exacerbating Cardiac Toxicity. Mol Pharmacol 88:512-23
Kukreja, Rakesh C (2014) Ataxia-telangiectasia mutated kinase: a potential new target for suppressing inflammation in heart failure? J Am Heart Assoc 3:e001591

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