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 ? ?
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