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

基本信息

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
项目类别：
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

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 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呼吸肌和膈肌的发育而受到限制患者的功能障碍。阿霉素引起的通气障碍是一种使人衰弱的疾病，可促进出现呼吸困难、疲劳和运动不耐受。虽然 DOX 诱导呼吸的机制不足之处尚不清楚，以往的工作表明通气功能障碍的发生率很大与隔膜吸收的 DOX 浓度相关。 DOX 在体内快速积累暴露后膈肌，它优先定位于线粒体并促进自由激进的生产。线粒体中自由基产生升高可能导致严重的破坏性事件导致细胞死亡，有证据表明，预防线粒体功能障碍足以减轻 DOX 对隔膜的毒性作用。因此，阐明线粒体的作用方式减少 DOX 的积累可能会导致开发出一种治疗方法来减轻 DOX 的肌肉毒性作用。对此，我们最近发现，在DOX之前进行耐力运动训练治疗足以减少线粒体中 DOX 的积累并保护膈肌和通气功能功能。虽然运动引起的膈肌水平降低的机制线粒体 DOX 未知，我们假设活动诱导外源性物质表达增加需要转运蛋白。具体来说，ATP 结合盒 (ABC) 转运蛋白是一类蛋白质具有促进化疗药物从隔膜流出的能力。此外，四线粒体定位的 ABC 转运蛋白在隔膜中表达（即 ABCB6、ABCB7、ABCB8 和 ABCB10)，所有这些都会随着运动而上调。因此，本提案的目标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，以及以确定它们预防 DOX 引起的呼吸功能障碍的治疗潜力。我们将完成这个通过测试以下具体目标：具体目标 1) 将确定运动介导的保护作用是否 DOX 诱导的呼吸功能障碍依赖于线粒体局部 ABC 转运水平的增加蛋白质；和特定目标 2) 将确定线粒体 ABC 转运蛋白是否过度表达膈肌足以减少 DOX 积累并预防 DOX 引起的呼吸功能障碍。