Doxorubicin cardiotoxicity and the protective effects of exercise

阿霉素(DOX)是一种用于治疗多种人类癌症的蒽环类抗生素， 包括急性白血病、淋巴瘤、胃癌、乳腺癌和卵巢癌。不幸的是，这种药物的临床应用 这种高效的抗癌药物由于患者心脏毒性的发展而受到限制。阿霉素- 诱导的心脏毒性是一种衰弱的情况，它会促进充血性心力衰竭的发生，导致 生活质量下降，发病率增加。而引起DOX心脏损害的机制 心功能不全尚不清楚，众所周知，心功能不全的发生率与 心脏摄取的DOX浓度。DOX在暴露后迅速在心脏组织内积聚， 在那里它优先定位于线粒体并促进自由基的产生。升高的自由基 有证据表明，线粒体的产生会导致严重的损伤事件，导致细胞死亡。 线粒体功能障碍的预防足以减轻DOX的心脏毒性效应。因此， 阐明减少DOX的线粒体积累的方法可能会导致发育 一种治疗方法来减轻DOX的心脏毒性效应。在这方面，我们最近发现， DOX治疗前的耐力运动训练足以减少DOX的线粒体积聚 并保护心脏功能。而导致运动诱导的水平下降的机制 心肌线粒体DOX的表达是未知的，我们假设活动诱导的表达增加 异种生物运输蛋白是必需的。具体地说，ATP结合盒(ABC)转运体是一类 具有促进化疗药物从心脏流出的能力的蛋白质。此外，还有四个 线粒体定位的ABC转运蛋白在心脏中表达(即ABCB6、ABCB7、ABCB8和ABCB10)， 所有这些都是随着运动而上调的。因此，这项提案的目标是确定这些因素的影响 转运蛋白在介导运动诱导的DOX从心脏排出中的作用 预防DOX引起的心功能不全的治疗潜力。我们将通过测试 以下具体目标：具体目标1)将确定运动诱导的对DOX毒性的保护是否 依赖于线粒体定位的ABC转运蛋白水平的增加；和特定的目标2)将决定 如果线粒体ABC转运蛋白在心脏中的过度表达足以减少心脏的DOX 蓄积和预防DOX引起的心脏毒性。

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.