Program Director/Principal Investigator (Last, First, Middie): Kukreja, Rakesh, ChanderPROJECT SUMMARY (See instructicns):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 establishedthat 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 cardiomyopathyand inhibits the growth of tumor in a xenograft model. The following new hypotheses will be tested: 1: cGMPdependent protein kinases (PKG) activated by chronic treatment with the long-acting PDE-5 inhibitor, tadalafil plays anessential role in protection against DOX-induced ventricular dysfunction through increased phosphorylation ofphospholamban. 2. Chronic treatment with tadalafil ameliorates DOX-induced persistent inhibition of Complex I ofmitochondrial respiratory chain which in tum reduces mitochondrial ROS generation, improves energetic status oftheDOX-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 clinicaltrials in humans receiving DOX-chemotherapy for hematologic and/or oncologic neoplasms.
Doxorubicin (DOX) is a powerful weapon for treatment of human cancers. However, this drug also causesmassive 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. PROJECT/PERFORiUIANCE SITE(S) (If additional space is needed, use
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