Induction of Cellular Antioxidants and Cardioprotection

描述（由申请人提供）：在过去的二十年中，癌症患者的生存率得到了极大的提高，这在很大程度上是由于有效的癌症治疗药物的发展，如阿霉素。然而，阿霉素的临床应用受到慢性治疗后心肌病发展的限制。大量证据表明，阿霉素诱导的心脏毒性是通过氧化机制发生的。在这方面，在培养细胞和动物中，各种外源性抗氧化剂的管理已被证明可以防止阿霉素诱导的心脏毒性。然而，化学试剂（药物）在心肌细胞中诱导内源性细胞抗氧化剂是否也对阿霉素诱导的心脏毒性提供保护还没有仔细研究。本研究项目的长期目标是制定合理的保护或治疗策略，以预防和/或延缓各种心脏疾病背后的氧化变性过程。这些策略依赖于对细胞抗氧化剂在心脏组织中的诱导性的理解。我们目前正在研究的假设是，心肌细胞中的内源性细胞抗氧化剂可以由独特的化学保护剂3h - 1,2 -二硫基-3-硫酮（D3T）诱导，并且在培养细胞和实验动物中增加的内源性抗氧化防御可以防止阿霉素诱导的心脏毒性，而不会干扰其所需的抗肿瘤活性。因此，本应用程序的具体目的是：(1)表征细胞抗氧化剂及其在小鼠心脏HL-1细胞中的诱导作用，HL-1细胞是最近建立的具有分化心肌细胞表型特征的心脏细胞系；(2)确定d3t诱导的细胞抗氧化剂对HL-1细胞多柔比星毒性的保护作用；(3)研究D3T在小鼠体内对心肌细胞抗氧化剂的诱导作用；(4)研究D3T给药小鼠对阿霉素心脏毒性和体内抗肿瘤活性的影响。实现上述目标将有助于更好地了解D3T对心脏抗氧化剂的诱导作用，以及D3T诱导的细胞抗氧化防御在氧化性心脏损伤中的保护作用——这不仅是由阿霉素引起的，也是由其他病理生理过程引起的，如缺血再灌注

DESCRIPTION (provided by applicant): 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