Doxorubicin cardiotoxicity and the protective effects of exercise

阿霉素心脏毒性和运动的保护作用

• 批准号: 10162657
• 负责人: Ashley Smuder
• 金额: $ 39.88万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 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/10162657
• 关键词: ABCB6 gene; ATP-Binding Cassette Transporters; ATP-binding cassette transport; Acute leukemia; Address; Animals; Anthracycline; Antibiotics; 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; Prognosis; 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; overexpression; preconditioning; prevent; protective effect; reduce symptoms; translational study

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）是一种用于治疗人类癌症的蒽环类抗生素， 包括急性白血病，淋巴瘤，胃，乳腺癌和卵巢癌。不幸的是，临床使用 由于患者的心脏毒性发展，这种高效的抗癌药受到限制。阿霉素 - 诱导心脏毒性是一种令人衰弱的疾病，可促进充血性心力衰竭的发作，导致 减少生活质量和发病率的增加。而导致DOX引起的心脏的机制 功能障碍尚不清楚，众所周知，心脏功能障碍的发生率与 心脏吸收的dox的浓度。暴露后，DOX在心脏组织中迅速积累 它优先将其定位于线粒体并促进自由基生产。自由基升高 线粒体的生产会导致严重的破坏事件，导致细胞死亡，证据表明 预防线粒体功能障碍足以减轻DOX的心脏毒性作用。所以， 阐明可以减少线粒体积累的方式可能导致发展 一种治疗方法来减轻DOX的心脏毒性作用。在这方面，我们最近发现 DOX治疗之前的耐力运动训练足以减少DOX的线粒体积累 并保留心脏功能。而导致运动水平降低的机制 心脏线粒体DOX的尚不清楚，我们假设活动引起的表达增加了 需要异生物传输蛋白。具体而言，ATP结合盒（ABC）转运蛋白是一类 蛋白质具有促进心脏化学疗法外排的能力。而且，四个 线粒体定位的ABC转运蛋白在心脏中表达（即ABCB6，ABCB7，ABCB8和ABCB10）， 所有这些都被锻炼上调。因此，该提议的目的是确定这些效果 在介导运动引起的DOX从心脏中挤出的过程中运输蛋白质，并确定它们 预防DOX诱导心脏功能障碍的治疗潜力。我们将通过测试 以下特定目的：具体目标1）将确定运动引起的对DOX毒性的保护是否是 取决于线粒体定位的ABC转运蛋白水平的增加；和特定目标2）确定 如果心脏中线粒体ABC转运蛋白的过表达足以减少心脏DOX 积累并防止DOX诱导的心脏毒性。