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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA139843-05
Application #
8298618
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (J1))
Program Officer
Alley, Michael C
Project Start
2008-09-25
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$261,900
Indirect Cost
$77,648
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Yarana, Chontida; Carroll, Dustin; Chen, Jing et al. (2018) Extracellular Vesicles Released by Cardiomyocytes in a Doxorubicin-Induced Cardiac Injury Mouse Model Contain Protein Biomarkers of Early Cardiac Injury. Clin Cancer Res 24:1644-1653
Thomas, Theresa Currier; Beitchman, Joshua A; Pomerleau, Francois et al. (2017) Acute treatment with doxorubicin affects glutamate neurotransmission in the mouse frontal cortex and hippocampus. Brain Res 1672:10-17
Yarana, Chontida; St Clair, Daret K (2017) Chemotherapy-Induced Tissue Injury: An Insight into the Role of Extracellular Vesicles-Mediated Oxidative Stress Responses. Antioxidants (Basel) 6:
Miriyala, Sumitra; Thippakorn, Chadinee; Chaiswing, Luksana et al. (2016) Novel role of 4-hydroxy-2-nonenal in AIFm2-mediated mitochondrial stress signaling. Free Radic Biol Med 91:68-80
Hayslip, John; Dressler, Emily V; Weiss, Heidi et al. (2015) Plasma TNF-? and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna-A Randomized, Cross-Over Clinical Study. PLoS One 10:e0124988
Zhao, Y; Miriyala, S; Miao, L et al. (2014) Redox proteomic identification of HNE-bound mitochondrial proteins in cardiac tissues reveals a systemic effect on energy metabolism after doxorubicin treatment. Free Radic Biol Med 72:55-65
Jorgenson, Tonia C; Zhong, Weixiong; Oberley, Terry D (2013) Redox imbalance and biochemical changes in cancer. Cancer Res 73:6118-23
Miriyala, Sumitra; Spasojevic, Ivan; Tovmasyan, Artak et al. (2012) Manganese superoxide dismutase, MnSOD and its mimics. Biochim Biophys Acta 1822:794-814
Fiorini, Ada; Sultana, Rukhsana; Barone, Eugenio et al. (2012) Lack of p53 affects the expression of several brain mitochondrial proteins: insights from proteomics into important pathways regulated by p53. PLoS One 7:e49846
Barone, Eugenio; Cenini, Giovanna; Sultana, Rukhsana et al. (2012) Lack of p53 decreases basal oxidative stress levels in the brain through upregulation of thioredoxin-1, biliverdin reductase-A, manganese superoxide dismutase, and nuclear factor kappa-B. Antioxid Redox Signal 16:1407-20

Showing the most recent 10 out of 21 publications