Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor
Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor
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熊果酸通过释放凋亡诱导因子诱导多柔比星耐药的 HepG2 细胞死亡
DOI：
10.1016/j.canlet.2010.06.010
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发表时间：
2010-12-01
期刊：
影响因子：
9.7
通讯作者：
Wu, Shihua
中科院分区：
文献类型：
--
作者：
Yang, Lu;Liu, Xiaozhuo;Wu, Shihua
熊果酸（Ursolic acid， UA）是一种从白花石斛（Oldenlondia diffusa）中分离得到的三萜类化合物，是一种治疗癌症的中药。研究发现熊果酸通过凋亡抑制阿霉素耐药人肝癌细胞（R-HepG2）的增殖，表现为磷脂酰丝氨酸外化、形态学改变和线粒体膜电位丧失。UA可激活Bak，但不能激活Bax，提示Bak可能在UA诱导的细胞凋亡中起重要作用。此外，UA诱导R-HepG2细胞死亡主要通过caspase-independent apoptosis-inducing factor （AIF）信号通路，这证明：(a)泛caspase抑制剂和特异性caspase抑制剂对UA的保护作用不明显；(b) UA处理引起AIF的核易位，在未处理的R-HepG2细胞中，AIF保留在线粒体中；(c)用人类aie特异性siRNA处理的细胞可以抵抗UA诱导的细胞死亡。此外，进一步的动物研究表明，UA在体内对R-HepG2细胞有效，对体重的影响很小，对肝脏、心脏和脾脏的损害很小。最重要的是，动物组织免疫组化染色也表明，UA还通过AIF信号通路显著抑制裸小鼠R-HepG2细胞的生长。2010爱思唯尔爱尔兰有限公司版权所有。
Ursolic acid (UA), a triterpenoid compound isolated previously from Oldenlondia diffusa, which is a Traditional Chinese Medicine used to treat cancer, was found to inhibit the proliferation of doxorubicin-resistant human hepatoma cell line (R-HepG2) through apoptosis as shown by externalization of phosphatidyl serine, morphological changes and loss of mitochondria) membrane potential. UA could activate Bak but not Bax, which implied that Bak may play an important role in UA-induced apoptosis. Furthermore, the death of R-HepG2 cells induced by UA was found to be mainly through the caspase-independent apoptosis-inducing factor (AIF) signaling pathway which was evidenced by: (a) the pan-caspase inhibitor and the specific caspase inhibitor had only modest protective effect against UA; (b) UA treatment caused the nuclear translocation of AIF, which is retained in the mitochondria in untreated R-HepG2 cells; (c) cells that had been treated with human AIE-specific siRNA could resist cell death induced by UA. In addition, a further animal study showed that UA was effective against R-HepG2 cells in vivo with negligible body weight loss and damage towards the liver, heart and spleen. Most importantly, immunohistochemical staining in animal tissues also suggested that UA also significantly inhibited the growth of R-HepG2 cells in nude mice through the AIF signaling pathway. (C) 2010 Elsevier Ireland Ltd. All rights reserved.