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 it's clinical efficacy, DOX's use is often limited due to dose-dependent cardiotoxicity. During the previous funding period, we established that phoshodiesterase-5 (PDE-5) inhibitor, sildenafil (Viagra) exerts powerful cardioprotective effect against DOX induced cardiomyopathy. The purpose of this 5-year renewal of MERIT Award application is to further study the;. mechanisms by which long-acting PDE-5 inhibitor, tadalafil protect the heart against DOX-induced cardiomyopathy and inhibits the growth of tumor in a xenograft model. The following new hypotheses will be tested: 1: cGMP dependent protein kinases (PKG) activated by chronic treatment with the long-acting PDE-5 inhibitor, tadalafil plays an essential role in protection against DOX-induced ventricular dysfunction through increased phosphorylation of phospholamban. 2. Chronic treatment with tadalafil ameliorates DOX-induced persistent inhibition of Complex I of mitochondrial respiratory chain which in turn reduces mitochondrial ROS generation, improves energetic status of the DOX-injured cardiac mitochondria and decreases cardiotoxicity of DOX via a NO/PKG dependent mechanism. 3: Tadalafil potentiates DOX-induced inhibition of tumor growth in nude mice bearing PC-3 or UCI-101 xenograft model. These studies will further extend our work on this project and provide valuable information leading to eventual clinical trials in humans receiving DOX-chemotherapy for hematologic and/or oncologic neoplasms.

Public Health Relevance

Doxorubicin (DOX) is a powerful weapon for treatment of human cancers. However, this drug also causes massive damage in the heart. We will study the protective effect and associated mechanisms by which long acting erectile dysfunction drug, Cialis protects the heart and also enhances the anti-cancer effect of DOX. We expect that will help patients who receive DOX-chemotherapy for various types of cancer.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Wong, Renee P
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Virginia Commonwealth University
Internal Medicine/Medicine
Schools of Medicine
United States
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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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