The survival rate of cancer patients has been dramatically improved over the last two decades, largely due to the development of effective cancer therapeutic agents, such as doxorubicin. However, the clinical use of doxorubicin is limited by the development of cardiomyopathy upon chronic treatment. Extensive evidence suggests that doxorubicin-induced cardiotoxicity occurs through an oxidative mechanism. In this regard, administration of a variety of exogenous antioxidants has been shown to protect against doxorubicin-induced cardiotoxicity in both cultured cells and animals. However, whether induction of endogenous cellular antioxidants by chemical agents (drugs) in cardiomyocytes also affords protection against doxorubicin-induced cardiotoxicity has not been carefully studied. The long-term objective of this research project is to develop rational protective or therapeutic strategies to prevent and/or retard the oxidative degenerative process underlying various cardiac diseases. These strategies rely on the understanding of the inducibility of cellular antioxidants in cardiac tissue. The hypothesis we are currently investigating is that the endogenous cellular antioxidants in cardiomyocytes can be induced by the unique chemoprotectant, 3H-1, 2-dithiole-3-thione (D3T) and that the increased endogenous antioxidant defenses protect against doxorubicin-induced cardiotoxicity in cultured cells and in experimental animals without interfering with its desired antitumor activity. Accordingly, the specific aims of this application are designed to: (1) characterize the cellular antioxidants and their inducibility by D3T in mouse cardiac HL-1 cells, a recently established cardiac cell line with phenotypic characteristics of differentiated cardiomyocytes; (2) determine the protective effects of D3T-induced cellular antioxidants against doxorubicin-mediated toxicity in HL-1 cells; (3) characterize the cardiac cellular antioxidants and their inducibility by D3T in mice in vivo; and (4) investigate the effects of D3T administration to mice on doxorubicin cardiotoxicity and antitumor activity in vivo. Fulfillment of the above aims will result in a greater understanding of the inducibility of cardiac antioxidants by D3T and the protective role of the D3T-induced cellular antioxidant defenses in oxidative cardiac injury _caused not only by doxorubicin but also by other pathophysiological processes, such as ischemia-reperfusion ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL071190-04
Application #
7304486
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Schwartz, Lisa
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2006-12-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$254,485
Indirect Cost
Name
Virginia College of Osteopathic Medicine
Department
Pharmacology
Type
Schools of Osteopathy
DUNS #
122566560
City
Blacksburg
State
VA
Country
United States
Zip Code
24060
Chen, Wei; Jia, Zhenquan; Zhu, Hong et al. (2010) Ethyl pyruvate inhibits peroxynitrite-induced DNA damage and hydroxyl radical generation: implications for neuroprotection. Neurochem Res 35:336-42
Jia, Zhenquan; Zhu, Hong; Li, Yunbo et al. (2010) Potent inhibition of peroxynitrite-induced DNA strand breakage and hydroxyl radical formation by dimethyl sulfoxide at very low concentrations. Exp Biol Med (Maywood) 235:614-22
Jia, Zhenquan; Misra, Bhaba R; Zhu, Hong et al. (2009) Upregulation of cellular glutathione by 3H-1,2-dithiole-3-thione as a possible treatment strategy for protecting against acrolein-induced neurocytotoxicity. Neurotoxicology 30:1-9
Jia, Zhenquan; Zhu, Hong; Vitto, Michael J et al. (2009) Alpha-lipoic acid potently inhibits peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation: implications for the neuroprotective effects of alpha-lipoic acid. Mol Cell Biochem 323:131-8
Chen, Wei; Zhu, Hong; Jia, Zhenquan et al. (2009) Inhibition of peroxynitrite-mediated DNA strand cleavage and hydroxyl radical formation by aspirin at pharmacologically relevant concentrations: implications for cancer intervention. Biochem Biophys Res Commun 390:142-7
Jia, Zhenquan; Zhu, Hong; Li, Yunbo et al. (2009) Cruciferous nutraceutical 3H-1,2-dithiole-3-thione protects human primary astrocytes against neurocytotoxicity elicited by MPTP, MPP(+), 6-OHDA, HNE and acrolein. Neurochem Res 34:1924-34
Zhu, Hong; Jia, Zhenquan; Zhou, Kequan et al. (2009) Cruciferous dithiolethione-mediated coordinated induction of total cellular and mitochondrial antioxidants and phase 2 enzymes in human primary cardiomyocytes: cytoprotection against oxidative/electrophilic stress and doxorubicin toxicity. Exp Biol Med (Maywood) 234:418-29
Jia, Zhenquan; Zhu, Hong; Misra, Bhaba R et al. (2008) Dopamine as a potent inducer of cellular glutathione and NAD(P)H:quinone oxidoreductase 1 in PC12 neuronal cells: a potential adaptive mechanism for dopaminergic neuroprotection. Neurochem Res 33:2197-205
Zhu, Hong; Jia, Zhenquan; Zhang, Li et al. (2008) Antioxidants and phase 2 enzymes in macrophages: regulation by Nrf2 signaling and protection against oxidative and electrophilic stress. Exp Biol Med (Maywood) 233:463-74
Zhu, Hong; Jia, Zhenquan; Misra, Bhaba R et al. (2008) Nuclear factor E2-related factor 2-dependent myocardiac cytoprotection against oxidative and electrophilic stress. Cardiovasc Toxicol 8:71-85

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