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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.

在这里输入文本，即应用程序的新抽象信息。这部分的文本不能超过30行。