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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：
10594901
负责人：
THOMAS Lindsay CLANTON
金额：
$ 36.11万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594901
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 Lymphoma 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 Risk Reduction 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 prescription exercise training experimental study heart function heart preservation 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.

多柔比星（DOX）是一种蒽环类抗生素，用于治疗广谱人类癌症，包括急性白血病、淋巴瘤、胃癌、乳腺癌和卵巢癌。不幸的是，这种高效的抗癌药物由于在患者中产生心脏毒性而受到限制。阿霉素- 诱导的心脏毒性是一种使人衰弱的病症，其促进充血性心力衰竭的发作，导致生活质量下降，发病率上升。虽然负责DOX诱导的心脏心功能不全的发生率尚不清楚，但众所周知，心功能不全的发生率与心功能不全的发生率密切相关。心脏吸收的DOX浓度。DOX在暴露后在心脏组织内迅速积累，在那里它优先定位于线粒体并促进自由基的产生。自由基升高在线粒体中的产生可以导致严重的破坏性事件，导致细胞死亡，有证据表明，线粒体功能障碍的预防足以减弱DOX的心脏毒性作用。因此，我们认为，阐明减少DOX线粒体积累的方法可能会导致减轻DOX心脏毒性作用的治疗方法。在这方面，我们最近发现，在DOX治疗之前进行耐力运动训练足以减少DOX的线粒体积累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的表达是未知的，我们假设活动诱导的DOX表达的增加，需要异生物质转运蛋白。具体地，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，四在心脏中表达位于心脏的ABC转运蛋白（即ABCB 6、ABCB 7、ABCB 8和ABCB 10），所有这些都随着运动而上调。因此，本提案的目标是确定这些措施的效果，转运蛋白在介导运动诱导的DOX从心脏排出中的作用，并确定其预防DOX诱导的心功能障碍的治疗潜力。我们将通过测试具体目标1）将确定运动诱导的针对DOX毒性的保护是否依赖于增加的水平，以提高本地化的ABC转运蛋白;和具体目标2）将决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 积累和防止DOX诱导的心脏毒性。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of Exercise Preconditioning on Doxorubicin-Induced Liver and Kidney Toxicity in Male and Female Rats.

DOI：
10.3390/ijms241210222
发表时间：
2023-06-16
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
通讯作者：

Consideration of Sex as a Biological Variable in the Development of Doxorubicin Myotoxicity and the Efficacy of Exercise as a Therapeutic Intervention.

DOI：
10.3390/antiox10030343
发表时间：
2021-02-25
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
0
作者：
Montalvo RN;Doerr V;Nguyen BL;Kelley RC;Smuder AJ
通讯作者：
Smuder AJ

Exercise and Doxorubicin Modify Markers of Iron Overload and Cardiolipin Deficiency in Cardiac Mitochondria.

DOI：
10.3390/ijms24097689
发表时间：
2023-04-22
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Montalvo, Ryan N.;Boeno, Franccesco P.;Dowllah, Imtiaz M.;Moritz, Cesar E. Jacintho;Nguyen, Branden L.;Doerr, Vivian;Bomkamp, Matthew P.;Smuder, Ashley J.
通讯作者：
Smuder, Ashley J.

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness.

DOI：
10.18632/oncotarget.27748
发表时间：
2020-09-22
期刊：
Oncotarget
影响因子：
0
作者：
Smuder AJ;Roberts BM;Wiggs MP;Kwon OS;Yoo JK;Christou DD;Fuller DD;Szeto HH;Judge AR
通讯作者：
Judge AR