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，这是您应用程序的新摘要信息。本节必须不超过30行文本。抗癌疗法，例如阿霉素（DOX）等蒽环类药物，对许多形式的恶性肿瘤有效。尽管如此，不幸的是，它们还可以导致依赖剂量依赖的心肌病，最终导致心力衰竭。目前尚无防止和/或管理这种蒽环类药物毒性（AIC）的最佳策略。活性氧（ROS）和线粒体功能障碍的增加是AIC的两个主要特征。但是，当前的抗氧化剂疗法无法预防DOX诱导的心肌病，而线粒体靶向的疗法只是作为一种吸引人的选择而出现。该提案，靶向线粒体的水硫化物供体来治疗蒽环类诱导的心脏毒性，重点是开发新的供体分子，这些分子产生了水溶（RSSH），以便对AIC进行潜在的治疗。这些新认识的反应性硫种类可以保护细胞免受破坏性剂和应力的影响。该提案有两个具体的目标。第一个目的涉及合成和优化两种不同类别的线粒体靶向的RSSH供体，可用于生物学研究。第二个目的研究了RSSH在维持或增强癌细胞中DOX功效的同时保护DOX诱导的心脏毒性的机制，重点是氧化应激衰减，线粒体功能和还原应力。比较还将与非靶向的RSSH供体和Dexrazoxane（DRZ）进行比较，Dexrazoxane（DRZ）是目前唯一针对AIC的FDA批准的治疗方法。该提案的总体目标是对新型保护RSSH的机械理解，可以防止DOX诱导的心脏毒性。