Schisandrin B prevents doxorubicin-induced cardiotoxicity via enhancing glutathione redox cycling
Schisandrin B prevents doxorubicin-induced cardiotoxicity via enhancing glutathione redox cycling
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DOI：
10.1158/1078-0432.ccr-07-1579
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发表时间：
2007-11-15
影响因子：
11.5
通讯作者：
Hu, Xun
中科院分区：
文献类型：
--
作者：
Li, Ling;Pan, Qiangrong;Hu, Xun
目的：剂量累积性心脏毒性和新出现的癌性细胞凋亡/耐药是限制蒽环类抗生素（尤其是阿霉素）疗效的两大障碍。我们试图证明五味子素B （schisandrin B， p -糖蛋白和多药耐药相关蛋白1的双重抑制剂）是否可以防止阿霉素诱导的心脏毒性，前提是Sch B是谷胱甘肽氧化还原循环的增强剂，可能会减弱阿霉素诱导的心肌细胞氧化应激。实验设计：小鼠或大鼠单次注射多柔比星（25mg /kg，每日1次），加或不加Sch B预处理，从血清中心肌酶的释放、丙二醛的形成、基质金属蛋白酶的激活、左心室结构损伤、死亡率和心功能等方面评价Sch B对多柔比星所致心脏损伤的保护作用。结果：Sch B预处理能显著减弱doxo rubici诱导的上述各方面的卡毒性。其潜在机制与Sch B维持心肌细胞谷胱甘肽和超氧化物歧化酶以及谷胱甘肽氧化还原循环的关键酶（谷胱甘肽过氧化物酶、谷胱甘肽还原酶和谷胱甘肽转移酶）的活性有关，这些酶可以中和阿霉素引起的氧化应激。结论：据我们所知，Sch B是迄今为止唯一被证明具有心脏保护剂功能的分子，同时也是p糖蛋白和多药耐药相关蛋白1的双重抑制剂，可能适用于治疗癌症，特别是涉及阿霉素或其同类的多药耐药癌症。
Purpose: The dose-cumulative cardiotoxicties and the emerging cancerous apoptotic/drug resistance are two major obstacles limiting the efficacy of anthracycline antibiotics, notably doxorubicin. We attempted to prove if schisandrin B (Sch B), a dual inhibitor of P-glycoprotein and multidrug resistance - associated protein 1, could protect against doxorubicin -induced cardiotoxicity, on the premise that Sch B is an enhancer of glutathione redox cycling that may attenuate doxorubicin-induced oxidative stress in the cardiomyocytes.Experimental Design: Mice or rat were dosed with a single injection of doxorubicin (25 mg/kg, i.p.) with or without pretreatment of Sch B. The protective roles of Sch B against doxorubicin-induced cardiac damage were evaluated on the aspects of the release of cardiac enzymes into serum, the formation of malondialdehyde, the activation of matrix metalloproteinase, the structural damage in the left ventricles, the mortality rates, and the cardiac functions.Results: Pretreatment of Sch B significantly attenuated doxo rubici n -induced card iotoxic ities on all the aspects listed above. The underlying mechanism was associated with the effect of Sch B on maintaining the cardiomyocytic glutathione and the activities of superoxide dismutase, and the key enzymes (glutathione peroxidase, glutathione reductase, and glutathione transferase) responsible for glutathione redox cycling, which neutralized doxorubicin-incluced oxidative stress.Conclusion: To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a dual inhibitor of P-glycoprotein and multidrug resistance - associated protein 1, which is potentially applicable to treat cancers, especially the multidrug-resistant cancers involving doxorubicin or its kin.