title: Baicalein protects against doxorubicin-induced cardiotoxicity by attenuation of mitochondrial oxidant injury and JNK activation.
abstract: 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.
authors: Emergency Resuscitation Center, Section of Emergency Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors: Wei-Tien
authors: WT
authors: Chang
authors: Jing
authors: J
authors: Li
authors: Hsien-Hao
authors: HH
authors: Haung
authors: Huiping
authors: H
authors: Liu
authors: Mei
authors: M
authors: Han
authors: Srinivasan
authors: S
authors: Ramachandran
authors: Chang-Qing
authors: CQ
authors: Li
authors: Willard W
authors: WW
authors: Sharp
authors: Kimm J
authors: KJ
authors: Hamann
authors: Chun-Su
authors: CS
authors: Yuan
authors: Terry L Vanden
authors: TL
authors: Hoek
authors: Zuo-Hui
authors: ZH
authors: Shao
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