Cardiotoxicity is a major complication of cancer treatment in protocols involving adriamycin (ADR), radiation, and high doses of cyclophosphamide (cytoxan). Because ADR and radiation are the most frequently used agents in the treatment of cancer, and cytoxan is also used in preparation of patients for bone marrow transplantation, efforts to overcome the dose limiting toxicities of these agents is likely to be beneficial for many cancer patients. The ultimate goal of this research is to develop an antioxidant-based pharmacological intervention for cancer therapy associated cardiac injury. Many studies have been conducted which suggest that both reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced in vivo by cancer therapeutic agents. However, the contribution of these ROS/RNS to the development of cardiac injury and the mechanism by which ROS/RNS mediates cardiac toxicity is unclear. We hypothesize that removal of superoxide radicals in the mitochondria is the critical step in protection against ROS/RNS-induced cardiac toxicity and tumor necrosis factor (TNF)-modulated cardiac injury during cancer therapy. To test this hypothesis, expression of MnSOD and GPX in the mitochondria of heart tissue will be elevated by transgenic manipulations, and the level of inducible nitric oxide synthase (iNOS) will be manipulated by targeted gene disruptions. The effects of the anticancer agents, ADR, cytoxan, and ionizing radiation on heart tissue will be examined in transgenic mice expressing increased individual or combined MnSOD (MnSOD-Tg) and mitochondrial GPX (mGPX-Tg) activity as well as in mice deficient in the inducible form of nitric oxide synthase (iNOS-KO). Cardiac injury will be assessed by determining the production of oxidatively damaged products, the respiratory function of isolated mitochondria, the formation of ultrastructural and histopathological lesions, as well as the extent of cardiomyocyte injury or cell death. The role of TNF in therapy-induced cardiac toxicity will be examined in TNF receptors knockout mice (TNFRs-KO) that express the human MnSOD transgenes (MnSOD-Tg/TNFRs-KO) using the same molecular, biochemical, and pathological end points. The results obtained from this study should demonstrate clearly how ROS/RNS contribute to cardiac toxicity and suggest potential points for pharmacological intervention of cardiac injury during cancer treatments.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Medicine
United States
Zip Code
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
Cole, Marsha P; Tangpong, Jitbanjong; Oberley, Terry D et al. (2014) Nuclear interaction between ADR-induced p65 and p53 mediates cardiac injury in iNOS (-/-) mice. PLoS One 9:e89251
Joshi, G; Aluise, C D; Cole, M P et al. (2010) Alterations in brain antioxidant enzymes and redox proteomic identification of oxidized brain proteins induced by the anti-cancer drug adriamycin: implications for oxidative stress-mediated chemobrain. Neuroscience 166:796-807
Tangpong, J; Sompol, P; Vore, M et al. (2008) Tumor necrosis factor alpha-mediated nitric oxide production enhances manganese superoxide dismutase nitration and mitochondrial dysfunction in primary neurons: an insight into the role of glial cells. Neuroscience 151:622-9
Joshi, Gururaj; Hardas, Sarita; Sultana, Rukhsana et al. (2007) Glutathione elevation by gamma-glutamyl cysteine ethyl ester as a potential therapeutic strategy for preventing oxidative stress in brain mediated by in vivo administration of adriamycin: Implication for chemobrain. J Neurosci Res 85:497-503
Tangpong, Jitbanjong; Cole, Marsha P; Sultana, Rukhsana et al. (2007) Adriamycin-mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain. J Neurochem 100:191-201
Cole, Marsha P; Chaiswing, Luksana; Oberley, Terry D et al. (2006) The protective roles of nitric oxide and superoxide dismutase in adriamycin-induced cardiotoxicity. Cardiovasc Res 69:186-97
Lien, Yu-Chin; Noel, Teresa; Liu, Hua et al. (2006) Phospholipase C-delta1 is a critical target for tumor necrosis factor receptor-mediated protection against adriamycin-induced cardiac injury. Cancer Res 66:4329-38
Lien, Yu-Chin; Lin, Shu-Mei; Nithipongvanitch, Ramaneeya et al. (2006) Tumor necrosis factor receptor deficiency exacerbated Adriamycin-induced cardiomyocytes apoptosis: an insight into the Fas connection. Mol Cancer Ther 5:261-9
Tangpong, Jitbanjong; Cole, Marsha P; Sultana, Rukhsana et al. (2006) Adriamycin-induced, TNF-alpha-mediated central nervous system toxicity. Neurobiol Dis 23:127-39

Showing the most recent 10 out of 18 publications