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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：
10386915
负责人：
Ashley Smuder
金额：
$ 36.27万
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/10386915
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

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）是一种用于治疗多种人类癌症的蒽环类抗生素，