Adriamycin (ADM) is one of the most effective chemotherapeutic agents used against verity of cancers. Despite its clinical efficacy, the drug is therapeutically associated wih selective toxicity to the heart. Patients with ADM therapy often develop delayed cardiomyopathy and overt congestive heart failure. In the past decade, considerable efforts have been made to develop a therapy which could block ADM cardio-toxicity, but still no effective therapy is available to combat an establish ADM cardiomyopathy. Cardiac transplantation remains the only definitive solution to improve survival of patients with irreversible ADM cardiomyopathy. The underlying mechanism of this drug toxicity is not yet fully understood, but it is generally believe that increased production of reactive oxygen species (ROS) from mitochondria is involved. Because discontinuation of ADM therapy for a cancer patient is difficult, new understanding is needed to define the underlying mechanism causing this drug toxicity, and to identify new therapeutic targets which could be used to protect the heart from ADM cardiomyopathy. My laboratory has specific interest in sirtuins, which are capable of protecting the heart from variou pathological stimuli. Recently, we identified a sirtuin isoform, SIRT3 which protects cardiomyocytes from oxidative stress-mediated cell death. SIRT3-deficent mice develop cardiomyopathy associated with interstitial fibrosis, and transgenic mice with cardiac-specific over expression of SIRT3 are protected from developing catecholamine-induced cardiomyopathy and heart failure. We also found that SIRT3 levels are significantly reduced during ADM cardio-toxicity, and over expression of SIRT3 protects hearts from ADM-mediated loss of cardiac function. Furthermore, our preliminary data show that ADM-cardio-toxicity is associated with massive acetylation of mitochondrial proteins, and that this effect can be blocked by over expression of SIRT3. These observations led us to hypothesize that SIRT3 has the potential to protect the heart from ADM mediated cardiac injury. Therefore, by maintaining or elevating intracellular levels of SIRT3 cardiomyopathy resulting from ADM therapy can be prevented. We will test this hypothesis in the following three aims. (1) Study whether SIRT3 activation can block ADM-mediated death of cardiomyocytes and differentiation of cardiac fibroblasts to myofibroblasts and the development of cardiomyopathy in mice. (2) Determine the underlying mechanisms through which SIRT3 protects the heart from ADM-mediated cardiomyopathy. (3) Study whether pharmacological candidates capable of activating endogenous SIRT3 levels hold the potential to block ADM cardiomyopathy without compromising anti-cancer activity of the drug. A successful outcome of these three aims will advance our understanding of the basic mechanism causing ADM cardiomyopathy, and that this may guide us to develop new therapeutic strategies to combating selective toxicity of anti- cancer drugs to the heart.

Public Health Relevance

Anticancer drugs often exert serious side effects to the heart. Patients receiving adriamycin (ADM) anti-cancer therapy develop delayed cardiomyopathy, which is a precursor to congestive heart failure. Besides cardiac transplantation, no effective therapy is presently available to reverse an established ADM cardiomyopathy. My laboratory has identified a molecule called SIRT3, which protects the heart from various oxidative stresses. This project is designed to test the hypothesis whether SIRT3 activation can block development of ADM cardiomyopathy without compromising anti-cancer activity of the drug.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL117041-01
Application #
8422349
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Shah, Monica R
Project Start
2013-06-01
Project End
2017-04-30
Budget Start
2013-06-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$426,031
Indirect Cost
$156,391
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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