Induction of Cellular Antioxidants and Cardioprotection

描述(申请人提供)：在过去的二十年中，癌症患者的存活率有了显著的提高，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引起的心脏毒性是通过氧化机制发生的。在这方面，在培养的细胞和动物中，给予各种外源抗氧化剂已被证明对阿霉素引起的心脏毒性具有保护作用。然而，用化学试剂(药物)在心肌细胞中诱导内源性细胞抗氧化剂是否也能保护心肌细胞对抗阿霉素引起的心脏毒性还没有得到仔细的研究。该研究项目的长期目标是开发合理的保护或治疗策略，以防止和/或延缓各种心脏疾病潜在的氧化退化过程。这些策略依赖于对心脏组织中细胞抗氧化剂诱导性的了解。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被独特的化学保护剂~3H-1，2-二硫醇-3-硫酮(D3T)诱导，并且增加的内源性抗氧化剂防御在培养细胞和实验动物中对抗阿霉素诱导的心脏毒性，而不会干扰其预期的抗肿瘤活性。因此，本应用的具体目的是：(1)鉴定D3T诱导的细胞抗氧化剂及其在小鼠心脏HL-1细胞中的诱导活性；(2)测定D3T诱导的细胞抗氧化剂对阿霉素介导的HL-1细胞毒性的保护作用；(3)研究D3T对小鼠心脏细胞抗氧化剂的作用及其在小鼠体内的诱导作用；(4)研究D3T对小鼠多柔比星心脏毒性和体内抗肿瘤活性的影响。上述目标的实现将使我们更好地理解D3T对心脏抗氧化剂的诱导作用，以及D3T诱导的细胞抗氧化剂防御在氧化心脏损伤中的保护作用--不仅是由阿霉素引起的，而且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