Mitochondria-Targeted Hydropersulfide Donors to Treat Anthracycline-Induced Cardiotoxicity

在此输入文本，它是您的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，如多柔比星(DOX)等蒽环类药物，对多种形式的恶性肿瘤都有效。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/或管理这种由蒽环类药物引起的心脏毒性(AIC)的最佳策略。活性氧(ROS)升高和线粒体功能障碍是AIC的两个主要特征。然而，目前的抗氧化剂疗法无法预防DOX引起的心肌病，而线粒体靶向疗法才刚刚成为一种有吸引力的替代疗法。这项建议，线粒体靶向的过硫化物供体用于治疗蒽环类药物引起的心脏毒性，重点是开发产生过硫化物(RSSH)的新型供体分子，以潜在地治疗AIC。这些新发现的活性硫物种可以保护细胞免受损害剂和压力的影响。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线粒体靶向RSSH供体，这些供体适合于生物学研究。第二个目的是研究RSSH在维持或增强癌细胞中DOX疗效的同时，保护心脏细胞免受DOX诱导的心脏毒性的机制(S)，重点是氧化应激减弱、线粒体功能和还原应激。还将与非线粒体靶向RSSH供体和Dexrazoxane(DRZ)进行比较，Dexrazoxane(DRZ)是FDA目前批准的唯一治疗AIC的药物。这项建议的总体目标是从机制上理解RSSH提供的针对DOX诱导的心脏毒性的新保护。

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.