Analysis of redox and apoptotic effects of anthracyclines to delineate a cardioprotective strategy.
Analysis of redox and apoptotic effects of anthracyclines to delineate a cardioprotective strategy.
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DOI：
10.1007/s00280-015-2879-4
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发表时间：
2015-12
影响因子：
3
通讯作者：
Chandra J
中科院分区：
文献类型：
--
作者：
Fulbright JM;Egas-Bejar DE;Huh WW;Chandra J
蒽环类药物的毒性副作用限制了它们作为有效化疗药物的应用。蒽环类抗生素诱导的心脏毒性机制的一种模型归因于细胞内活性氧（ROS）的产生。然而，这一理论受到质疑，因为一些心脏保护策略包括使用抗氧化剂，但没有显着的临床益处。我们试图确定蒽环类药物暴露后，在体内和体外细胞内活性氧的测量是否可以提供一种手段，设计更有效的抗氧化剂心脏保护计划。在接触蒽环类药物的白血病小鼠和接受蒽环类药物治疗的患者的外周血单核细胞中评估细胞内ROS水平。还在心肌细胞和白血病细胞系中进行了体外细胞死亡诱导和ROS水平的比较。使用抗氧化剂进行ROS阻断，并评估对细胞死亡的影响。小鼠血液和代表性患者样本中ROS升高与心肌细胞坏死和射血分数降低相关。在体外，蒽环类药物在急性白血病细胞和心肌细胞中的细胞毒性作用的比较揭示了不同的动力学细胞死亡诱导和依赖于氧化应激。虽然在急性白血病细胞和心肌细胞中观察到细胞凋亡，但抗氧化剂N-乙酰半胱氨酸保护心肌细胞而不是急性白血病细胞免受蒽环类药物的细胞毒性。我们的研究结果指向重新审视NAC作为心脏保护剂的使用，因为它似乎不会干扰蒽环类药物的细胞毒性作用。NAC已在临床上评估了心脏保护活性，但未来的试验必须确保包括足够的剂量，时间表和氧化应激标志物的掺入。
Cardiotoxic side effects of anthracyclines limit their use as effective chemotherapeutics. One model for the mechanism of anthracycline induced cardiotoxicity is attributed to the generation of intracellular reactive oxygen species (ROS). However this theory has been questioned because several cardioprotective strategies have included the use of antioxidants without significant clinical benefit. We sought to determine whether measurement of intracellular reactive oxygen species after anthracycline exposure in vivo and in vitro could provide a means for designing more effective antioxidant cardioprotective schemes. Intracellular levels of ROS were assessed in peripheral blood mononuclear cells from leukemia bearing mice exposed to anthracyclines and in patients receiving anthracyclines. Comparison of cell death induction and ROS levels were also conducted in vitro in cardiomyocyte and leukemia lines. ROS blockade using antioxidants was conducted and effects on cell death were assessed. Elevated ROS in blood of mice and representative patient samples correlated with cardiomyocyte necrosis and decreased ejection fraction. In vitro, comparison of the cytotoxic effects of anthracyclines in acute leukemia cells and in cardiomyocytes revealed distinct kinetics of cell death induction and dependence upon oxidative stress. Although apoptotic cell death was observed in both acute leukemia cells and cardiomyocytes, the antioxidant N-acetylcysteine protected cardiomyocytes but not acute leukemia cells from anthracycline cytotoxicity. Our findings point towards revisiting the use of NAC as a cardioprotective agent since it does not appear to interfere with the cytotoxic action of anthracyclines. NAC has been evaluated clinically for cardioprotective activity but future trials must ensure that adequate dose, scheduling and incorporation of markers of oxidative stress are included.