Doxorubicin-induced respiratory dysfunction and the protective effects of exercise

阿霉素引起的呼吸功能障碍及运动的保护作用

• 批准号: 10449081
• 负责人: Ashley Smuder
• 金额: $ 37.44万
• 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: 2019-09-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449081
• 关键词: ABCB6 gene; ATP-Binding Cassette Transporters; ATP-binding cassette transport; Acute leukemia; Address; Animals; Anthracycline; Antibiotics; Antineoplastic Agents; Antioxidants; Antisense Oligonucleotides; Area; Attenuated; Biological; Cancer Patient; Carrier Proteins; Cell Death; Cells; Clinical; Consensus; Cytochrome c Reductase; Development; Disease Progression; Doxorubicin; Dyspnea; Event; Exercise; Exposure to; Fatigue; Fiber; Foundations; Free Radicals; Functional disorder; Future; Goals; Homeostasis; Human; Impairment; Incidence; Iron; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Mitochondria; Molecular; Molecular Target; Muscle; Muscle Weakness; Myopathy; Outcome; Oxidation-Reduction; Oxidative Stress; Pathology; Patients; Physical activity; Play; Prevention; Prevention strategy; Production; Proteins; Public Health; Reactive Oxygen Species; Recombinant adeno-associated virus (rAAV); Regulation; Respiration Disorders; Respiratory Diaphragm; Respiratory Failure; Respiratory Insufficiency; Respiratory Muscles; Respiratory Signs and Symptoms; Respiratory physiology; Risk; Risk Factors; Role; Saline; Skeletal Muscle; Testing; Therapeutic; Toxic effect; Up-Regulation; Work; Xenobiotics; adeno-associated viral vector; anti-cancer; cancer therapy; chemotherapeutic agent; chemotherapy; effective therapy; endurance exercise; exercise intolerance; exercise training; experimental study; leukemia/lymphoma; malignant breast neoplasm; malignant stomach neoplasm; mitochondrial dysfunction; novel strategies; overexpression; preconditioning; preservation; pressure; prevent; protective effect; reduce symptoms; respiratory; 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 respiratory and diaphragm muscle dysfunction in patients. Doxorubicin-induced ventilatory impairment is a debilitating condition that promotes the onset dyspnea, fatigue and exercise intolerance. While the mechanisms responsible for DOX-induced respiratory insufficiency are unclear, previous work demonstrates that the incidence of ventilatory dysfunction greatly correlates to the concentration of DOX taken up by the diaphragm. DOX accumulates rapidly within the diaphragm muscle 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 toxic effects of DOX on the diaphragm. 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 myotoxic 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 diaphragm and ventilatory function. While the mechanisms responsible for the exercise-induced reduction in the levels of diaphragm 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 diaphragm. Moreover, four mitochondria-localized ABC transporters are expressed in the diaphragm (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 diaphragm, and to determine their therapeutic potential to prevent DOX-induced respiratory dysfunction. We will accomplish this by testing the following specific aims: Specific Aim 1) will determine if exercise-mediated protection against DOX-induced respiratory dysfunction is dependent on increased levels of mitochondria-localized ABC transport proteins; and Specific Aim 2) will determine if overexpression of mitochondrial ABC transport proteins in the diaphragm is sufficient to reduce DOX accumulation and prevent DOX-induced respiratory dysfunction.

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 由于呼吸道和隔膜肌肉的发展，这种高效的抗癌药受到限制 患者功能障碍。阿霉素引起的通气障碍是一种令人衰弱的状况，可促进 发作呼吸困难，疲劳和运动不耐受。而导致DOX诱导呼吸道的机制 不足是不清楚的，先前的工作表明，通气功能障碍的发生率很大 与隔膜吸收的DOX的浓度相关。 DOX在 暴露后的隔膜肌肉，优先将其定位于线粒体并促进免费 根本生产。线粒体中升高的自由基生产会导致严重的破坏性事件 导致细胞死亡，证据表明预防线粒体功能障碍足以足以 减轻DOX对隔膜的毒性作用。因此，阐明线粒体的方式 可以减少DOX的积累可能会导致一种治疗方法来减轻治疗方法 DOX的肌毒性作用。在这方面，我们最近发现DOX之前的耐力运动训练 治疗足以减少DOX的线粒体积累并保留隔膜和通风 功能。而导致运动引起的隔膜水平降低的机制 线粒体DOX尚不清楚，我们假设活性引起的异种表达的增加增加了 需要运输蛋白。具体而言，ATP结合盒（ABC）转运蛋白是一类蛋白质 具有促进化学治疗药物从隔膜促进的能力。而且，四个 线粒体定位的ABC转运蛋白在diaphragm中表达（即ABCB6，ABCB7，ABCB8和 ABCB10），所有这些都在运动上上调。因此，该提议的目的是建立 这些转运蛋白在介导运动引起的DOX从隔膜中挤出的作用，并 确定它们的治疗潜力，以防止DOX诱导的呼吸功能障碍。我们将实现这一目标 通过测试以下特定目的：特定目标1）将确定锻炼介导的保护是否涉及 DOX诱导的呼吸功能障碍取决于线粒体定位的ABC转运水平的增加 蛋白质；和特定的目标2）确定线粒体ABC转运蛋白的过表达是否在 隔膜足以减少DOX的积累并防止DOX诱导的呼吸功能障碍。