SPACE PROVIDED. Heart disease is a major dose limiting factor of cancer therapy that uses anthracycline as a component of the protocol. Generation of reactive oxygen species (ROS) has been implicated in the toxicity of a large number of therapeutic agents including those containing the redox cycling groups. The goal of this study is to identify novel mechanisms that lead to cardioprotection during cancer treatment. Our studies of animal and isolated cardiomyocytes indicate that overexpression of the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) protects the heart against adriamycin (ADR)-induced cardiac injury. Interestingly, ADR treatment leads to an increase in circulating levels of tumor necrosis factor alpha (TNF)t a pleiotropic cytokine that has also been shown to produce ROS. We also found that ADR- induced cardiac injury is associated with translocation of p53 to the mitochondria and interaction of p53 with MnSOD. Based on these novel findings we hypothesize that ADR toxicity is the result of a cascade that involves ADR producing direct oxidative stress that sequentially leads to TNF production and amplification of oxidative stress in mitochondria. To test this hypothesis, cardiac tissue and cardiomyocytes isolated from MnSOD deficient, wild type, and mice overexpressing MnSOD as well as p53 deficient, p53 deficient with MnSOD deficient, and p53 deficient overexpressing MnSOD mice of the same inbred background will be used as models.
Aims 1 and 2 will test the hypothesis that ADR toxicity is the result of a cascade that involves ADR and its metabolites producing direct oxidative stress that sequentially leads to TNF production and amplification of oxidative stress in heart tissues and in cardiomyocytes.
Aim 3 will test the hypothesis that oxidative stress initiated in mitochondria serves as a death signal, which regulates p53 translocation and its mitochondrial-mediated transcription dependent and independent pathways .
Aim 4 will test the hypothesis that selective modulation of cellular antioxidant status or TNF levels alters ADR-induced cardiac njury in experimental therapeutic settings. The results from these studies will provide important insights for mechanistic-based pharmacological interventions to reduce cancer therapy-associated cardiac injury. Because the extensive use of ADR, translation of these findings will not only improve the quality of life but will also enhance the probability of cancer free survival for a large number of cancer patients.
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