Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection?
Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection?
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DOI：
10.1016/j.pcad.2010.06.007
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发表时间：
2010-09
影响因子：
9.1
通讯作者：
Lim, Chee Chew
中科院分区：
文献类型：
--
作者：
Sawyer, Douglas B.;Peng, Xuyang;Chen, Billy;Pentassuglia, Laura;Lim, Chee Chew
蒽环类抗生素自发现以来的50多年里挽救了许多癌症患者的生命。其使用的主要限制是剂量限制性心脏毒性。致力于了解蒽环类药物心脏效应的生化基础，目前已提供了几种临床用途：使用的策略：限制剂量暴露;将蒽环类药物包封在脂质体中，以减少心肌摄取;与铁螯合剂右雷佐生同时给药，以减少游离铁催化的活性氧物质形成;修饰蒽环类药物结构，以减少心肌毒性。尽管做出了这些努力，蒽环类药物诱导的心力衰竭仍继续发生，并导致发病率和死亡率。我们无法预测和预防蒽环类药物的心脏毒性，部分原因是分子和细胞机制仍然存在争议和不完全理解。研究蒽环类抗生素在体外心肌细胞和小动物体内的作用已经证明了几种形式的心脏损伤，目前尚不清楚这些如何转化为临床环境。鉴于临床证据表明，蒽环类药物暴露后发生肌细胞死亡，表现为血清肌钙蛋白升高，肌细胞死亡似乎是蒽环类药物诱导的心脏损伤的可能机制。肌细胞损伤的其他机制包括以正常肌节结构破坏为特征的细胞“肌减少症”的发展。蒽环类药物抑制几种心脏转录因子的表达，这可能在肌细胞死亡和肌肉减少症的发展中起作用。巨肌丝蛋白肌联蛋白的降解可能是导致肌丝降解加速的重要近端步骤。临床上已经注意到蒽环类药物与靶向erbB 2受体酪氨酸激酶的新型癌症治疗之间的有趣相互作用。现在有证据表明，erbB 2信号响应于配体神经调节蛋白调节蒽环类药物通过多药耐药蛋白进入细胞的摄取。因此，上调心脏神经调节蛋白信号可能是限制心肌蒽环类药物损伤的一种策略。此外，通过对这种和其他心肌保护信号的内源性活性进行某种测量，可以改善对蒽环类药物损伤个体风险的评估。
Anthracycline antibiotics have saved the lives of many cancer victims in the 50 plus years since their discovery. A major limitation of their use is the dose-limiting cardiotoxicity. Efforts focusing on understanding the biochemical basis for anthracycline cardiac effects have provided several strategies currently in clinical use: limit dose exposure; encapsulate anthracyclines in liposomes to reduce myocardial uptake; administer concurrently with the iron chelator dexrazoxane to reduce free iron-catalyzed reactive oxygen species formation; modification of anthracycline structure in an effort to reduce myocardial toxicity. In spite of these efforts, anthracycline-induced heart failure continues to occur with consequences for both morbidity and mortality. Our inability to predict and prevent anthracycline cardiotoxicity is in part due to the fact that the molecular and cellular mechanisms remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes in vitro and small animals in vivo have demonstrated several forms of cardiac injury, and it remains unclear how these translate to the clinical setting. Given the clinical evidence that myocyte death occurs after anthracycline exposure in the form of elevations in serum troponin, myocyte cell death appears to be a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular ‘sarcopenia’ characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. There is now evidence that erbB2 signaling in response to the ligand neuregulin regulates anthracycline uptake into cells via the multidrug-resistance protein. Therefore upregulation of cardiac neuregulin signaling may be one strategy to limit myocardial anthracycline injury. Moreover, assessing an individual’s risk for anthracycline injury may be improved by having some measure of endogenous activity of this and other myocardial protective signals.
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影响因子：
5
作者：
Fukazawa, R;Miller, TA;Sawyer, DB
通讯作者：
Sawyer, DB
影响因子：
3.6
作者：
Chung, Ka Young;Walker, Jeffery W.
通讯作者：
Walker, Jeffery W.
DOI：
10.1083/jcb.153.2.413
发表时间：
2001-04-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bang ML;Mudry RE;McElhinny AS;Trombitás K;Geach AJ;Yamasaki R;Sorimachi H;Granzier H;Gregorio CC;Labeit S
通讯作者：
Labeit S
影响因子：
3.8
作者：
Helmes, M;Lim, CC;Sawyer, DB
通讯作者：
Sawyer, DB
影响因子：
45.3
作者：
Ewer, MS;Vooletich, MT;Lenihan, DJ
通讯作者：
Lenihan, DJ