Mitochondria-Targeted Hydropersulfide Donors to Treat Anthracycline-Induced Cardiotoxicity

在此输入文本，它是应用程序的新摘要信息。此部分不得超过30行文本。 抗癌疗法，如蒽环类药物如阿霉素（DOX），对许多形式的恶性肿瘤有效。然而，不幸的是，它们也可能导致进行性剂量依赖性心肌病，最终导致心力衰竭。目前还没有预防和/或管理这种蒽环类药物诱导的心脏毒性（AIC）的最佳策略。活性氧（ROS）增加和线粒体功能障碍是AIC的两个主要特征。然而，目前的抗氧化疗法未能预防DOX诱导的心肌病，而靶向治疗则刚刚成为一种有吸引力的替代疗法。该提案，线粒体靶向过氧化氢供体治疗蒽环类药物诱导的细胞毒性，重点是开发新的供体分子，产生过氧化氢（RSSH），以治疗AIC的潜力。这些新认识到的活性硫物质可以保护细胞免受破坏剂和压力的影响。该提案有两个具体目标。第一个目标涉及合成和优化两种不同类型的靶向RSSH供体，适合生物学研究。第二个目的检查RSSH在心脏细胞中保护免受DOX诱导的心脏毒性同时维持或增强DOX在癌细胞中的功效的机制，重点是氧化应激衰减、线粒体功能和还原应激。还将与非线粒体靶向RSSH供体和右雷佐生（DRZ）进行比较，右雷佐生是目前FDA批准的唯一治疗AIC的药物。该提案的总体目标是对RSSH提供的针对DOX诱导的心脏毒性的新保护的机制理解。

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Anti-cancer therapies, such as anthracyclines like doxorubicin (DOX), are effective against many forms of malignancies. Still, unfortunately, they can also lead to progressive dose-dependent cardiomyopathy and eventually heart failure. There is no current optimal strategy for preventing and/or managing this anthracycline-induced cardiotoxicity (AIC). An increase in reactive oxygen species (ROS) and mitochondrial dysfunction are two main features of AIC. However, current antioxidant therapies fail to prevent DOX-induced cardiomyopathy, while mitochondria-targeted therapies are just emerging as an appealing alternative. This proposal, Mitochondria-Targeted Hydropersulfide Donors to Treat Anthracycline-Induced Cardiotoxicity, focuses on developing novel donor molecules that generate hydropersulfides (RSSH) to treat AIC potentially. These newly recognized reactive sulfur species can protect cells from damaging agents and stresses. The proposal has two Specific Aims. The first aim involves synthesizing and optimizing two different classes of mitochondria-targeted RSSH donors amenable for biological studies. The second aim examines the mechanism(s) whereby RSSH protects against DOX- induced cardiotoxicity in cardiac cells while maintaining or potentiating DOX efficacy in cancer cells, focusing on oxidative stress attenuation, mitochondrial function, and reductive stress. Comparisons will also be made with non-mitochondria- targeted RSSH donors and dexrazoxane (DRZ), the only currently FDA-approved treatment for AIC. The overall goal of this proposal is a mechanistic understanding of the novel protection RSSH affords against DOX-induced cardiotoxicity.