Anticancer effects of wogonin in both estrogen receptor-positive and -negative human breast cancer cell lines in vitro and in nude mice xenografts
Anticancer effects of wogonin in both estrogen receptor-positive and -negative human breast cancer cell lines in vitro and in nude mice xenografts
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DOI：
10.1002/ijc.23182
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发表时间：
2008-02-15
影响因子：
6.4
通讯作者：
Kong, Gu
中科院分区：
文献类型：
--
作者：
Chung, Heekyoung;Jung, Youn -Mi;Kong, Gu
汉黄芩素是一种植物单黄酮类化合物，据报道可抑制多种肿瘤中的细胞生长和/或诱导细胞凋亡。在此，我们研究了汉黄芩素在人乳腺癌中的体外和体内抗癌作用及其相关机制。研究了汉黄芩素对雌激素受体（ER）阳性和阴性人乳腺癌细胞的增殖、细胞周期进程和凋亡的影响。研究了口服汉黄芩素对无胸腺裸鼠肿瘤异种移植物生长的体内作用。通过免疫印迹分析与汉黄芩素生物效应相关的分子变化。汉黄芩素(50-200μM)以时间和浓度依赖性方式减弱细胞生长，与其ER状态无关。细胞凋亡增强并伴随着 PARP 和 Caspase 3 裂解以及促凋亡 Bax 蛋白的上调。观察到 Akt 活性受到抑制，其底物 GSK-3 beta 和 p27 的磷酸化减少。 Cyclin D1 表达的抑制表明 Akt 介导的规范 Writ 信号通路下调。 ER 阳性细胞中 ER 表达下调，而 ER 阴性 SK-BR-3 细胞中 c-ErbB2 表达及其活性受到抑制。给小鼠喂食汉黄芩素，治疗 4 周后，T47D 和 MD-AMB-231 异种移植物的肿瘤生长抑制率高达 88%，且没有任何毒性。由于汉黄芩素在体外和体内均有效，我们的新发现开启了汉黄芩素作为针对 ER 阳性和阴性乳腺癌的有效治疗和/或化学预防剂的可能性，特别是针对更具侵袭性和对激素治疗耐药的 ER 阴性类型。 (C) 2007 Wiley-Liss, Inc.
Wogonin is a plant monoflavonoid which has been reported to inhibit cell growth and/or induce apoptosis in various tumors. Herein, we investigated the in vitro and in vivo anticancer effects and associated mechanisms of wogonin in human breast cancer. Effects of wogonin were examined in estrogen receptor (ER)-positive and -negative human breast cancer cells in culture for proliferation, cell cycle progression, and apoptosis. The in vivo effect of oral wogonin was examined on tumor xenograft growth in athymic nude mice. The molecular changes associated with the biological effects of wogonin were analyzed by immunoblotting. Cell growth was attenuated by wogonin (50-200 mu M), independently of its ER status, in a time- and concentration-dependent manner. Apoptosis was enhanced and accompanied by upregulation of PARP and Caspase 3 cleavages as well as proapoptotic Bax protein. Akt activity was suppressed and reduced phosphorylation of its substrates, GSK-3 beta and p27, was observed. Suppression of Cyclin D1 expression suggested the downregulation of the Akt-mediated canonical Writ signaling pathway. ER expression was downregulated in ER-positive cells, while c-ErbB2 expression and its activity were suppressed in ER-negative SK-BR-3 cells. Wogonin feeding to mice showed inhibition of tumor growth of T47D and MD-AMB-231 xenografts by up to 88% without any toxicity after 4 weeks of treatment. As wogonin was effective both in vitro and in vivo, our novel findings open the possibility of wogonin as an effective therapeutic and/or chemopreventive agent against both ER-positive and -negative breast cancers, particularly against the more aggressive and hormonal therapy-resistant ER-negative types. (C) 2007 Wiley-Liss, Inc.