A Biophysical Systems Approach to Identifying the Pathways of Acute and Chronic Doxorubicin Mitochondrial Cardiotoxicity.
A Biophysical Systems Approach to Identifying the Pathways of Acute and Chronic Doxorubicin Mitochondrial Cardiotoxicity.
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DOI：
10.1371/journal.pcbi.1005214
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发表时间：
2016-11
影响因子：
4.3
通讯作者：
Niederer S
中科院分区：
文献类型：
--
作者：
de Oliveira BL;Niederer S
蒽环类多柔比星的临床应用受到其与线粒体功能障碍相关的心脏毒性的限制。氧化还原循环、线粒体DNA损伤和电子传递链抑制已被确定为潜在的毒性机制。然而，这些拟议机制中的每一个的相对作用仍然没有得到充分的理解。本研究的目的是确定这些途径中的哪一个独立或组合负责阿霉素毒性。一个国家的最先进的线粒体的数学模型，包括柠檬酸循环，电子传递链和活性氧的生产和清除系统进行了扩展，纳入一个新的表示线粒体DNA损伤和修复。进行了计算机模拟实验，以量化急性和慢性毒性阶段每种毒性机制对线粒体功能障碍的贡献。模拟预测氧化还原循环在阿霉素心脏毒性中的作用较小。电子传递链抑制是超治疗剂量急性毒性的主要途径，在线粒体浓度高于200μM时具有致死性。直接线粒体DNA损伤是治疗剂量慢性心脏毒性的主要途径，导致进行性和不可逆的长期线粒体功能障碍。阿霉素是一种有效的抗癌药物，但其疗效受到累积剂量依赖性心脏毒性的限制。药物心脏毒性涉及多个途径，但其潜在机制尚未完全阐明。在这里，我们开发了一个计算模型来研究多柔比星线粒体心脏毒性，这是第一次允许在一个统一的框架中对不同的假设进行系统的检验。通过对多种毒性机制作用的定量比较，可以确定电子传递链是急性毒性的主要原因，而直接损伤线粒体DNA是慢性心脏毒性的主要途径。这是开发新的抗肿瘤疗法、毒性筛选和开发减轻阿霉素心脏毒性的治疗方法的关键一步。
The clinical use of the anthracycline doxorubicin is limited by its cardiotoxicity which is associated with mitochondrial dysfunction. Redox cycling, mitochondrial DNA damage and electron transport chain inhibition have been identified as potential mechanisms of toxicity. However, the relative roles of each of these proposed mechanisms are still not fully understood. The purpose of this study is to identify which of these pathways independently or in combination are responsible for doxorubicin toxicity. A state of the art mathematical model of the mitochondria including the citric acid cycle, electron transport chain and ROS production and scavenging systems was extended by incorporating a novel representation for mitochondrial DNA damage and repair. In silico experiments were performed to quantify the contributions of each of the toxicity mechanisms to mitochondrial dysfunction during the acute and chronic stages of toxicity. Simulations predict that redox cycling has a minor role in doxorubicin cardiotoxicity. Electron transport chain inhibition is the main pathway for acute toxicity for supratherapeutic doses, being lethal at mitochondrial concentrations higher than 200μM. Direct mitochondrial DNA damage is the principal pathway of chronic cardiotoxicity for therapeutic doses, leading to a progressive and irreversible long term mitochondrial dysfunction. Doxorubicin is a potent anticancer drug, but its efficacy is limited by a cumulative dose-dependent cardiotoxicity. Multiple pathways are involved in the drug cardiotoxicity, however, the underlying mechanisms are still not fully elucidated. Here we developed a computational model to study doxorubicin mitochondrial cardiotoxicity, which allowed for the first time, a systematic test of different hypothesis in a unified framework. By quantitatively comparing the effect of multiple toxicity mechanisms, we could identify that electron transport chain is the main cause of acute toxicity, while direct damage to the mitochondrial DNA is the principal pathway of chronic cardiotoxicity. This is a crucial step in developing new antitumor therapies, toxicity screens and developing treatments to mitigate doxorubicin cardiotoxicity.
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DOI：
10.1186/s40959-016-0012-4
发表时间：
2016-03-03
期刊：
Cardio-oncology (London, England)
影响因子：
--
作者：
De Angelis A;Urbanek K;Cappetta D;Piegari E;Ciuffreda LP;Rivellino A;Russo R;Esposito G;Rossi F;Berrino L
通讯作者：
Berrino L
影响因子：
3.4
作者：
Gauthier, Laura D.;Greenstein, Joseph L.;Winslow, Raimond L.
通讯作者：
Winslow, Raimond L.
影响因子：
105.7
作者：
BONADONNA, G;MONFARDINI, S;FOSSATIB.F
通讯作者：
FOSSATIB.F
影响因子：
7.4
作者：
Bazil, Jason N.;Pannala, Venkat R.;Beard, Daniel A.
通讯作者：
Beard, Daniel A.
影响因子：
3.4
作者：
Bazil, Jason N.;Beard, Daniel A.;Vinnakota, Kalyan C.
通讯作者：
Vinnakota, Kalyan C.