Doxorubicin cardiotoxicity and the protective effects of exercise

阿霉素心脏毒性和运动的保护作用

基本信息

批准号：
9986064
负责人：
Ashley Smuder
金额：
$ 36.66万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9986064
关键词：
ABCB6 gene ATP-Binding Cassette Transporters ATP-binding cassette transport Acute leukemia Address Animals Anthracycline Anthracyclines Antineoplastic Agents Antioxidants Antisense Oligonucleotides Attenuated Biological Cancer Patient Cardiac Cardiomyopathies Cardiotoxicity Carrier Proteins Cell Death Cells Clinical Congestive Heart Failure Consensus Cytochrome c Reductase Development Disease Progression Doxorubicin Event Exercise Exposure to Fatigue Foundations Free Radicals Future Goals Heart Homeostasis Human Incidence Iron Lead Malignant Neoplasms Malignant neoplasm of ovary Measures Mediating Mitochondria Molecular Molecular Target Morbidity - disease rate Myocardial Myocardial dysfunction Oxidation-Reduction Oxidative Stress Pathology Patients Physical activity Play Prevalence Prevention Prevention strategy Production Proteins Public Health Quality of life Reactive Oxygen Species Recombinant adeno-associated virus (rAAV)Regulation Risk Factors Role Saline Solid Neoplasm Testing Therapeutic Tissues Toxic effect Up-Regulation Xenobiotics adeno-associated viral vector anti-cancer cardioprotection cardiovascular disorder risk chemotherapeutic agent chemotherapy effective therapy endurance exercise exercise training experimental study heart function heart preservation leukemia/lymphoma malignant breast neoplasm malignant stomach neoplasm mitochondrial dysfunction novel strategies outcome forecast overexpression preconditioning prevent protective effect protein transport reduce symptoms translational study

项目摘要

Doxorubicin (DOX) is an anthracycline antibiotic used in the treatment of a broad spectrum of human cancers, including acute leukemia, lymphomas, stomach, breast and ovarian cancers. Unfortunately, the clinical use of this highly efficacious anticancer drug is limited due to the development of cardiotoxicity in patients. Doxorubicin- induced cardiotoxicity is a debilitating condition that promotes the onset of congestive heart failure, resulting in reduced quality of life and increased morbidity. While the mechanisms responsible for DOX-induced cardiac dysfunction are unclear, it is well known that the incidence of cardiac dysfunction greatly correlates to the concentration of DOX taken up by the heart. DOX accumulates rapidly within cardiac tissue following exposure, where it preferentially localizes to the mitochondria and promotes free radical production. Elevated free radical production in the mitochondria can lead to severe damaging events resulting in cell death, and evidence suggests that prevention of mitochondrial dysfunction is sufficient to attenuate the cardiotoxic effects of DOX. Therefore, elucidating ways in which the mitochondrial accumulation of DOX can be reduced could result in the development of a therapeutic approach to mitigate the cardiotoxic effects of DOX. In this regard, we recently discovered that endurance exercise training prior to DOX treatment is sufficient to reduce the mitochondrial accumulation of DOX and preserve cardiac function. While the mechanisms responsible for the exercise-induced reduction in the levels of cardiac mitochondrial DOX are unknown, we hypothesize that activity-induced increases in the expression of xenobiotic transport proteins are required. Specifically, the ATP-binding cassette (ABC) transporters are a class of proteins with the capability of facilitating the efflux of chemotherapeutics from the heart. Moreover, four mitochondria-localized ABC transporters are expressed in the heart (i.e. ABCB6, ABCB7, ABCB8 and ABCB10), all of which are upregulated with exercise. Therefore, the goal of this proposal is to establish the effects of these transport proteins in mediating the exercise-induced extrusion of DOX from the heart, and to determine their therapeutic potential to prevent DOX-induced cardiac dysfunction. We will accomplish this by testing the following specific aims: Specific Aim 1) will determine if exercise-induced protection against DOX toxicity is dependent on increased levels of mitochondria-localized ABC transporters; and Specific Aim 2) will determine if overexpression of mitochondrial ABC transport proteins in the heart is sufficient to reduce cardiac DOX accumulation and prevent DOX-induced cardiotoxicity.

阿霉素 (DOX) 是一种蒽环类抗生素，用于治疗多种人类癌症，包括急性白血病、淋巴瘤、胃癌、乳腺癌和卵巢癌。不幸的是，临床使用这种高效的抗癌药物由于对患者产生心脏毒性而受到限制。阿霉素- 诱发的心脏毒性是一种使人衰弱的疾病，会促进充血性心力衰竭的发生，从而导致生活质量下降，发病率增加。虽然 DOX 诱发心脏的机制心功能障碍的发生率尚不清楚，但众所周知，心功能障碍的发生与心脏吸收的 DOX 浓度。 DOX 暴露后在心脏组织内迅速积聚，它优先定位于线粒体并促进自由基的产生。自由基升高有证据表明，线粒体的产生可能导致严重的破坏性事件，从而导致细胞死亡预防线粒体功能障碍足以减轻 DOX 的心脏毒性作用。所以，阐明减少 DOX 线粒体积累的方法可能会导致开发减轻 DOX 心脏毒性作用的治疗方法。对此，我们最近发现 DOX 治疗前的耐力运动训练足以减少 DOX 的线粒体积累并保护心脏功能。虽然运动引起的水平降低的机制心脏线粒体 DOX 的表达尚不清楚，我们假设活动诱导的表达增加需要外源物质转运蛋白。具体来说，ATP 结合盒 (ABC) 转运蛋白是一类具有促进化疗药物从心脏流出的能力的蛋白质。此外，四线粒体定位的 ABC 转运蛋白在心脏中表达（即 ABCB6、ABCB7、ABCB8 和 ABCB10），所有这些都会通过锻炼而上调。因此，本提案的目标是确定这些措施的影响转运蛋白介导运动引起的 DOX 从心脏中排出，并确定其预防 DOX 引起的心脏功能障碍的治疗潜力。我们将通过测试来实现这一点以下具体目标：具体目标 1) 将确定运动诱导的针对 DOX 毒性的保护作用是否有效依赖于线粒体定位 ABC 转运蛋白水平的增加；和具体目标 2) 将确定如果心脏中线粒体 ABC 转运蛋白的过度表达足以减少心脏 DOX 积累并防止 DOX 引起的心脏毒性。