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 hs 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 tum 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.

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 #
5R37HL051045-16
Application #
8212002
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wong, Renee P
Project Start
1995-08-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
16
Fiscal Year
2012
Total Cost
$399,821
Indirect Cost
$132,382
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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
Shalwala, Mona; Zhu, Shu-Guang; Das, Anindita et al. (2014) Sirtuin 1 (SIRT1) activation mediates sildenafil induced delayed cardioprotection against ischemia-reperfusion injury in mice. PLoS One 9:e86977
Toldo, Stefano; Das, Anindita; Mezzaroma, Eleonora et al. (2014) Induction of microRNA-21 with exogenous hydrogen sulfide attenuates myocardial ischemic and inflammatory injury in mice. Circ Cardiovasc Genet 7:311-20
Koka, Saisudha; Das, Anindita; Salloum, Fadi N et al. (2013) Phosphodiesterase-5 inhibitor tadalafil attenuates oxidative stress and protects against myocardial ischemia/reperfusion injury in type 2 diabetic mice. Free Radic Biol Med 60:80-8
Hoke, Nicholas N; Salloum, Fadi N; Kass, David A et al. (2012) Preconditioning by phosphodiesterase-5 inhibition improves therapeutic efficacy of adipose-derived stem cells following myocardial infarction in mice. Stem Cells 30:326-35
Kukreja, Rakesh C; Yin, Chang; Salloum, Fadi N (2011) MicroRNAs: new players in cardiac injury and protection. Mol Pharmacol 80:558-64
Zhu, Shu-Guang; Kukreja, Rakesh C; Das, Anindita et al. (2011) Dietary nitrate supplementation protects against Doxorubicin-induced cardiomyopathy by improving mitochondrial function. J Am Coll Cardiol 57:2181-9
Chau, Vinh Q; Salloum, Fadi N; Hoke, Nicholas N et al. (2011) Mitigation of the progression of heart failure with sildenafil involves inhibition of RhoA/Rho-kinase pathway. Am J Physiol Heart Circ Physiol 300:H2272-9
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
Ghosh, Siddhartha S; Salloum, Fadi N; Abbate, Antonio et al. (2010) Curcumin prevents cardiac remodeling secondary to chronic renal failure through deactivation of hypertrophic signaling in rats. Am J Physiol Heart Circ Physiol 299:H975-84

Showing the most recent 10 out of 36 publications