Preferential inhibition of hepatocellular carcinoma by the flavonoid Baicalein through blocking MEK-ERK signaling
Preferential inhibition of hepatocellular carcinoma by the flavonoid Baicalein through blocking MEK-ERK signaling
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DOI：
10.3892/ijo.2012.1510
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发表时间：
2012-09-01
影响因子：
5.2
通讯作者：
Li, Zong-Fang
中科院分区：
文献类型：
--
作者：
Liang, Rong-Rui;Zhang, Shu;Li, Zong-Fang
黄芩素是从黄芩或黄芩根中提取的精制黄酮类化合物。虽然先前的研究表明黄芩素具有体外抗肝癌活性，但其体内作用和作用机制仍不完全清楚。在本研究中，黄芩素在40-120 mU M的浓度范围内对三种肝癌细胞株有明显的细胞毒作用，而对一种正常肝细胞系的细胞毒作用较弱。与标准化疗药物5-氟尿嘧啶(5-FU)相比，黄芩素对肝癌细胞的作用更强，而对正常肝细胞的毒性更小。黄芩素显著降低线粒体跨膜电位，并激活caspase-9和caspase-3。用泛半胱氨酸氨基转移酶抑制剂阻断黄芩素诱导的细胞凋亡可部分减弱黄芩素诱导的肝细胞癌生长抑制。黄芩素治疗可显著抑制小鼠肝癌移植瘤的生长。用末端脱氧核苷酸转移酶dUTP缺口末端标记法(TUNEL)检测黄芩素对移植瘤的诱导凋亡作用。此外，黄芩素在体内外显著降低了MEK1、ERK1/2和Bad的磷酸化水平。人MEK1的过表达部分阻断了黄芩素诱导的生长抑制。因此，这些发现表明，黄芩素通过抑制MEK-ERK信号通路和诱导内源性细胞凋亡来优先抑制肝癌肿瘤的生长。
Baicalein is a purified flavonoid extracted from the roots of Scutellaria baicalensis or Scutellaria radix. Although previous studies have suggested that Baicalein possesses an in vitro anti-hepatocellular carcinoma activity, its in vivo effects and mechanisms of action are still not completely understood. In this study, Baicalein at concentrations of 40-120 mu M exhibited significant cytotoxicity to three hepatocellular carcinoma (HCC) cell lines but marginal cytotoxicity to a normal liver cell line in vitro. Compared to a standard chemotherapy drug, 5-fluorouracil (5-FU), Baicalein had greater effect on HCC cells but less toxicity on normal liver cells. Treatment with Baicalein dramatically reduced mitochondrial transmembrane potential, and activated caspase-9 and caspase-3. Blockade of Baicalein-induced apoptosis with a pan-caspase inhibitor partially attenuated Baicalein-induced growth inhibition in HCC. Baicalein treatment significantly inhibited tumor growth of HCC xenografts in mice. Induction of apoptosis was demonstrated in Baicalein-treated xenograft tumors by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Furthermore, Baicalein treatment dramatically decreased the levels of phosphorylation of MEK1, ERK1/2 and Bad in vitro and in vivo. Overexpression of human MEK1 partially blocked Baicalein-induced growth inhibition. Consequently, these findings suggest that Baicalein preferentially inhibits HCC tumor growth through inhibition of MEK-ERK signaling and by inducing intrinsic apoptosis.