Mitochondria-Targeted Hydropersulfide Donors to Treat Anthracycline-Induced Cardiotoxicity

线粒体靶向氢过硫化物供体治疗蒽环类药物引起的心脏毒性

基本信息

批准号：
10689759
负责人：
John P Toscano
金额：
$ 34.88万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10689759
关键词：
Address Adult Adverse effects Anthracycline Antineoplastic Agents Antioxidants Biochemical Biological Cancer Patient Cancer cell line Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cations Cells Clinical Cytoprotection Data Derivation procedure Dexrazoxane Disparity Donor Selection Dose Doxorubicin Evaluation Exposure to FDA approved Goals Heart failure Hydrogen Sulfide Hydrolysis In Vitro Link Malignant Neoplasms Mitochondria Mus Muscle Cells Oxidative Stress Pathway interactions Patients Reactive Oxygen Species Recommendation Shelter facility Stress Sulfur Testing Text Toxic effect anti-cancer antioxidant therapy antitumor effect attenuation cancer cell cancer therapy cell injury cell type esterase heart function lipophilicity mitochondrial dysfunction novel oxidative damage preservation prevent targeted treatment

项目摘要

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.

在此处输入文本，该文本是您的应用程序的新摘要信息。此部分的文本长度不得超过 30 行。抗癌疗法，例如阿霉素 (DOX) 等蒽环类药物，可有效对抗多种恶性肿瘤。但不幸的是，它们也可能导致进行性剂量依赖性心肌病，并最终导致心力衰竭。目前尚无预防和/或管理这种蒽环类药物引起的心脏毒性（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，目前的抗氧化疗法无法预防 DOX 诱发的心肌病，而线粒体靶向疗法才刚刚成为一种有吸引力的替代疗法。该提案名为“以线粒体为靶点的氢过硫化物供体来治疗蒽环类药物引起的心脏毒性”，重点是开发可产生氢过硫化物 (RSSH) 的新型供体分子，以潜在地治疗 AIC。这些新认识的活性硫物质可以保护细胞免受有害物质和压力的侵害。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别的线粒体靶向 RSSH 供体，适合生物学研究。第二个目标是研究 RSSH 保护心肌细胞免受 DOX 诱导的心脏毒性，同时维持或增强 DOX 对癌细胞的功效的机制，重点关注氧化应激减弱、线粒体功能和还原应激。还将与非线粒体靶向 RSSH 供体和右雷佐生 (DRZ) 进行比较，后者是目前 FDA 批准的唯一 AIC 治疗方法。该提案的总体目标是从机制上理解 RSSH 针对 DOX 诱导的心脏毒性提供的新型保护。