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Mitochondrial Determinants of Doxorubicin-Induced Cardiomyopathy
Circulation Research ( IF 20.1 ) Pub Date : 2020-03-26 , DOI: 10.1161/circresaha.119.314681
Kendall B. Wallace 1 , Vilma A. Sardão 2 , Paulo J. Oliveira 2
Affiliation  

Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly prescribed anthracyclines in the United States due to its broad spectrum of therapeutic efficacy. Interference with different mitochondrial processes is chief among the molecular and cellular determinants of doxorubicin cardiotoxicity, contributing to the development of cardiomyopathy. The present review provides the basis for the involvement of mitochondrial toxicity in the different functional hallmarks of anthracycline toxicity. Our objective is to understand the molecular determinants of a progressive deterioration of functional integrity of mitochondria that establishes a historic record of past drug treatments (mitochondrial memory) and renders the cancer patient susceptible to subsequent regimens of drug therapy. We focus on the involvement of doxorubicin-induced mitochondrial oxidative stress, disruption of mitochondrial oxidative phosphorylation, and permeability transition, contributing to altered metabolic and redox circuits in cardiac cells, ultimately culminating in disturbances of autophagy/mitophagy fluxes and increased apoptosis. We also suggest some possible pharmacological and nonpharmacological interventions that can reduce mitochondrial damage. Understanding the key role of mitochondria in doxorubicin-induced cardiomyopathy is essential to reduce the barriers that so dramatically limit the clinical success of this essential anticancer chemotherapy.

中文翻译:

阿霉素诱导的心肌病的线粒体决定因素

基于蒽环类的化学疗法可导致累积性和逐步发展的心肌病的发展。阿霉素因其广泛的治疗功效而成为美国处方最严格的蒽环类药物之一。阿霉素心脏毒性的分子和细胞决定因素中主要是干扰不同的线粒体过程,这有助于心肌病的发展。本综述提供了线粒体毒性参与蒽环类药物毒性的不同功能标志的基础。我们的目标是了解线粒体功能完整性进行性恶化的分子决定因素,该分子决定因素建立了过去药物治疗(线粒体记忆)的历史记录,并使癌症患者易于接受随后的药物治疗方案。我们专注于阿霉素诱导的线粒体氧化应激,线粒体氧化磷酸化的破坏和通透性转变的参与,从而导致心肌细胞代谢和氧化还原回路的改变,最终导致自噬/线粒体通量的紊乱和细胞凋亡的增加。我们还建议一些可能减少线粒体损伤的药理和非药理干预措施。
更新日期:2020-03-27
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