Baicalein protects against doxorubicin-induced cardiotoxicity by attenuation of mitochondrial oxidant injury and JNK activation.
Baicalein protects against doxorubicin-induced cardiotoxicity by attenuation of mitochondrial oxidant injury and JNK activation.
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DOI：
10.1002/jcb.23201
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发表时间：
2011-10
影响因子：
4
通讯作者：
Shao, Zuo-Hui
中科院分区：
文献类型：
--
作者：
Chang, Wei-Tien;Li, Jing;Haung, Hsien-Hao;Liu, Huiping;Han, Mei;Ramachandran, Srinivasan;Li, Chang-Qing;Sharp, Willard W.;Hamann, Kimm J.;Yuan, Chun-Su;Vanden Hoek, Terry L.;Shao, Zuo-Hui
阿霉素的心脏毒性限制了其在多种恶性肿瘤治疗中的临床应用。以往的研究表明，阿霉素相关的心脏毒性是由活性氧(ROS)诱导的细胞凋亡介导的。因此，我们研究了黄芩素，一种天然的抗氧化剂成分，是否可以减轻阿霉素诱导的ROS的产生和细胞死亡。在已建立的鸡心肌细胞模型上，阿霉素(10μM)以浓度和时间依赖的方式增加细胞死亡。ROS的生成以剂量-反应方式增加，并与线粒体膜电位的丧失有关。阿霉素还可增加DNA片段化，增加ROS敏感的促凋亡蛋白激酶c-jun氨基末端激酶(JNK)的磷酸化。联合应用黄芩素(25μM)和阿霉素24 h可显著减少ROS的产生(587±89A.U..与932 A.U..细胞死亡率(30.6±5.1%比46.8±8.3%，P<；0.01)。线粒体电位的消失和DNA片段化的增加也得到改善。随着细胞ROS和细胞凋亡的减少，黄芩素可减弱阿霉素诱导的JNK的磷酸化(1.7±0.3比3.0±0.4倍，P<；0.05)。用阿霉素和JNK抑制剂SP600125(10μM，24 h)共同处理心肌细胞，可降低JNK的磷酸化，提高细胞存活率，提示黄芩素对阿霉素心肌毒性的保护作用是通过激活JNK来实现的。重要的是，黄芩素同时治疗并不干扰阿霉素在人乳腺癌MCF-7细胞中的抗增殖作用。总而言之，黄芩素辅助治疗在不影响其抗癌效果的情况下，对阿霉素引起的心脏毒性提供了抗细胞凋亡的保护。
The cardiotoxicity of doxorubicin limits its clinical use in the treatment of a variety of malignancies. Previous studies suggest that doxorubicin-associated cardiotoxicity is mediated by reactive oxygen species (ROS)-induced apoptosis. We therefore investigated if baicalein, a natural antioxidant component of Scutellaria baicalensis, could attenuate ROS generation and cell death induced by doxorubicin. Using an established chick cardiomyocyte model, doxorubicin (10 μM) increased cell death in a concentration- and time-dependent manner. ROS generation was increased in a dose-response fashion and associated with loss of mitochondrial membrane potential. Doxorubicin also augmented DNA fragmentation and increased the phosphorylation of ROS-sensitive pro-apoptotic kinase c-Jun N-terminal kinase (JNK). Adjunct treatment of baicalein (25 μM) and doxorubicin for 24 h significantly reduced both ROS generation (587 ± 89 a.u. vs. 932 a.u. ± 121 a.u., P < 0.01) and cell death (30.6 ± 5.1% vs. 46.8 ± 8.3%, P < 0.01). The dissipated mitochondrial potential and increased DNA fragmentation were also ameliorated. Along with the reduction of ROS and apoptosis, baicalein attenuated phosphorylation of JNK induced by doxorubicin (1.7 ± 0.3 vs. 3.0 ± 0.4 fold, P < 0.05). Co-treatment of cardiomyocytes with doxorubicin and JNK inhibitor SP600125 (10 μM; 24 h) reduced JNK phosphorylation and enhanced cell survival, suggesting that the baicalein protection against doxorubicin cardiotoxicity was mediated by JNK activation. Importantly, concurrent baicalein treatment did not interfere with the anti-proliferative effects of doxorubicin in human breast cancer MCF-7 cells. In conclusion, baicalein adjunct treatment confers anti-apoptotic protection against doxorubicin-induced cardiotoxicity without compromising its anti-cancer efficacy.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
7.2
作者：
Psotová, J;Chlopcíková, S;Simánek, V
通讯作者：
Simánek, V
影响因子：
10.8
作者：
Liu, Tsun-Jui;Yeh, Yueh-Chiao;Lai, Hui-Chin
通讯作者：
Lai, Hui-Chin
影响因子：
9.7
作者：
Po, LS;Chen, ZY;Leung, LK
通讯作者：
Leung, LK
影响因子：
37.8
作者：
Li, K;Sung, RYT;Ng, PC
通讯作者：
Ng, PC