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.
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