Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers.
Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers.
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DOI：
10.1038/cddis.2016.418
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发表时间：
2017-01-19
影响因子：
9
通讯作者：
Fritz G
中科院分区：
文献类型：
--
作者：
Henninger C;Fritz G
接受蒽环类药物化疗的癌症患者有发生危及生命的慢性心脏毒性的风险，其病理生理学作用机制尚未完全了解。除了蒽环类药物诱导的充血性心力衰竭（CHF）主要是由活性氧产生引起的最常见的假设外，最近的数据表明拓扑异构酶II β（TOP2B）在CHF的病理生理学中起关键作用，拓扑异构酶II β是蒽环类药物中毒的主要靶点。由于FDA在2011年限制了唯一一种临床批准的心脏保护剂右雷佐生的使用，因此迫切需要替代的心脏保护措施。他汀类药物是抗炎和抗氧化药物，在临床上被广泛用于预防心血管疾病。它们表现出超越降胆固醇作用的多效性有益特性，其最可能依赖于小Ras同源（Rho）GTP酶的间接抑制。Rho GTCRac 1已被证明是调节促氧化NADPH氧化酶以及调节II型拓扑异构酶的主要因子。两者都被讨论在蒽环类药物诱导的CHF的病理生理学中发挥重要作用。因此，他汀类药物或新型Rac1抑制剂的标签外使用可能代表了一种有前途的药理学方法，通过干扰蒽环类药物诱导的心肌细胞死亡的关键机制来控制慢性心脏毒性。
Cancer patients receiving anthracycline-based chemotherapy are at risk to develop life-threatening chronic cardiotoxicity with the pathophysiological mechanism of action not fully understood. Besides the most common hypothesis that anthracycline-induced congestive heart failure (CHF) is mainly caused by generation of reactive oxygen species, recent data point to a critical role of topoisomerase II beta (TOP2B), which is a primary target of anthracycline poisoning, in the pathophysiology of CHF. As the use of the only clinically approved cardioprotectant dexrazoxane has been limited by the FDA in 2011, there is an urgent need for alternative cardioprotective measures. Statins are anti-inflammatory and anti-oxidative drugs that are clinically well established for the prevention of cardiovascular diseases. They exhibit pleiotropic beneficial properties beyond cholesterol-lowering effects that most likely rest on the indirect inhibition of small Ras homologous (Rho) GTPases. The Rho GTPase Rac1 has been shown to be a major factor in the regulation of the pro-oxidative NADPH oxidase as well as in the regulation of type II topoisomerase. Both are discussed to play an important role in the pathophysiology of anthracycline-induced CHF. Therefore, off-label use of statins or novel Rac1 inhibitors might represent a promising pharmacological approach to gain control over chronic cardiotoxicity by interfering with key mechanisms of anthracycline-induced cardiomyocyte cell death.