Flavonoids as protectors against doxorubicin cardiotoxicity:: Role of iron chelation, antioxidant activity and inhibition of carbonyl reductase
Flavonoids as protectors against doxorubicin cardiotoxicity:: Role of iron chelation, antioxidant activity and inhibition of carbonyl reductase
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DOI：
10.1016/j.bbadis.2007.05.002
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发表时间：
2007-09-01
影响因子：
6.2
通讯作者：
Kvasnickova, Eva
中科院分区：
文献类型：
--
作者：
Kaiserova, Helena;Simunek, Tomas;Kvasnickova, Eva
蒽环类抗生素(如阿霉素和柔红霉素)是最有效和应用最广泛的抗癌药物之一。不幸的是，它们的临床应用受到剂量依赖性心脏毒性的限制。黄酮类化合物是一类潜在的有吸引力的化合物，可以减轻由于其铁螯合、抗氧化剂和羰基还原酶抑制作用而产生的蒽环类药物的心脏毒性。然而，不同特征的黄酮类化合物对其心脏保护活性的相对贡献尚不清楚。采用10个黄酮类化合物，包括槲皮苷、槲皮苷、7-羟乙基芦丁苷(MonHER)和7个原始合成化合物，研究了它们对阿霉素心脏毒性的保护作用，以及它们对羰基还原、铁络合的抑制作用和抗氧化性能之间的关系。新生大鼠心肌细胞具有心肌保护作用，而H9c2成心肌细胞用于细胞毒性试验。用钙黄绿素比色法测定铁的络合作用，通过抑制脂质过氧化作用和清除羟基自由基活性来量化抗氧化作用和定点清除作用。在人肝细胞胞浆中检测了羰基还原酶的抑制作用。没有一种被测试的黄酮类化合物具有比参考心脏保护剂MonHER更好的心脏保护作用。然而，一种新合成的具有类似心脏保护作用的季铵类似物已被鉴定。目前还没有发现铁螯合和/或抗氧化效果与心脏保护潜力之间的直接联系。羰基还原酶抑制的主要作用似乎不太可能，因为该系列中最好的两种心脏保护剂只是弱还原酶抑制剂。(C)2007 Elsevier B.V.保留所有权利。
Anthracycline antibiotics (e.g. doxorubicin and daunorubicin) are among the most effective and widely used anticancer drugs. Unfortunately, their clinical use is limited by the dose-dependent cardiotoxicity. Flavonoids represent a potentially attractive class of compounds to mitigate the anthracycline cardiotoxicity due to their iron-chelating, antioxidant and carbonyl reductase-inhibitory effects. The relative contribution of various characteristics of the flavonoids to their cardioprotective activity is, however, not known. A series of ten flavonoids including quercetin, quercitrin, 7-inonohydroxyethylrutoside (monoHER) and seven original synthetic compounds were employed to examine the relationships between their inhibitory effects on carbonyl reduction, iron-chelation and antioxidant properties with respect to their protective potential against doxorubicin-induced cardiotoxicity. Cardioprotection was investigated in the neonatal rat ventricular cardiomyocytes whereas the H9c2 cardiomyoblast cells were used for cytotoxicity testing. Iron chelation was examined via the calcein assay and antioxidant effects and site-specific scavenging were quantified by means of inhibition of lipid peroxidation and hydroxyl radical scavenging activity, respectively. Inhibition of carbonyl reductases was assessed in cytosol from human liver. None of the flavonoids tested had better cardioprotective action than the reference cardioprotector, monoHER. However, a newly synthesized quaternary ammonium analog with comparable cardioprotective effects has been identified. No direct correlation between the iron-chelating and/or antioxidant effect and cardioprotective potential has been found. A major role of carbonyl reductase inhibition seems unlikely, as the best two cardioprotectors of the series are only weak reductase inhibitors. (c) 2007 Elsevier B.V. All rights reserved.