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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Koka, Saisudha; Aluri, Hema S; Xi, Lei et al. (2014) Chronic inhibition of phosphodiesterase 5 with tadalafil attenuates mitochondrial dysfunction in type 2 diabetic hearts: potential role of NO/SIRT1/PGC-1? signaling. Am J Physiol Heart Circ Physiol 306:H1558-68
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Koka, Saisudha; Das, Anindita; Zhu, Shu-Guang et al. (2010) Long-acting phosphodiesterase-5 inhibitor tadalafil attenuates doxorubicin-induced cardiomyopathy without interfering with chemotherapeutic effect. J Pharmacol Exp Ther 334:1023-30
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