Berberine inhibits human hepatoma cell invasion without cytotoxicity in healthy hepatocytes.
Berberine inhibits human hepatoma cell invasion without cytotoxicity in healthy hepatocytes.
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DOI：
10.1371/journal.pone.0021416
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zang L
中科院分区：
文献类型：
--
作者：
Liu B;Wang G;Yang J;Pan X;Yang Z;Zang L
传统化疗无法治愈转移性肝癌，主要是因为其高肝毒性。许多植物源性药物已被认为可以有效抑制肝癌细胞的侵袭。然而，针对侵袭性肝癌细胞的有效植物源制剂是否对健康肝细胞产生意想不到的细胞毒性的研究却被忽视了。这项研究表明，小檗碱在 HepG2 细胞中表现出显着的细胞毒性，主要是通过上调活性氧 (ROS) 的产生，但在正常的 Chang 肝细胞中无效。小檗碱通过抑制基质金属蛋白酶-9 (MMP-9) 表达对 HepG2 细胞发挥抗侵袭作用。此外，小檗碱能显着抑制PI3K-AKT和ERK通路的活性。 ERK 通路抑制剂 PD98059 或 AKT 通路抑制剂 LY294002 与小檗碱的联合治疗可协同降低 MMP-9 表达并抑制细胞侵袭。小檗碱增强ROS产生对其抑制PI3K-AKT和ERK通路活性以及MMP-9表达和HepG2细胞侵袭的作用没有影响。总之，我们的结果表明，小檗碱可能通过 PI3K-AKT 和 ERK 通路依赖性下调 MMP-9 表达，成为对抗侵袭性肝癌细胞的潜在替代品。这项研究还为研究基于植物源制剂的抗肿瘤侵袭疗法（同时考虑对健康细胞的损害）提供了以前被忽视的见解。
Conventional chemotherapy fails to cure metastatic hepatoma mainly due to its high hepatotoxicity. Many plant-derived agents have been accepted to effectively inhibit hepatoma cell invasion. However, the investigation that whether effectual plant-derived agents against invasive hepatoma cells exert unexpected cytotoxicity in healthy hepatocytes has been ignored. This study demonstrated that berberine exhibited significant cytotoxicity in HepG2 cells mainly through upregulation of reactive oxygen species (ROS) production but was ineffective in normal Chang liver cells. Berberine exerted anti-invasive effect on HepG2 cells through suppression of matrix metalloproteinase-9 (MMP-9) expression. Moreover, berberine could significantly inhibit the activity of PI3K-AKT and ERK pathways. Combination treatment of ERK pathway inhibitor PD98059 or AKT pathway inhibitor LY294002 and berberine could result in a synergistic reduction on MMP-9 expression along with an inhibition of cell invasion. Enhancement of ROS production by berberine had no influence on its suppressive effects on the activity of PI3K-AKT and ERK pathways, as well as MMP-9 expression and HepG2 cell invasion. In conclusion, our results suggest that berberine may be a potential alternative against invasive hepatoma cells through PI3K-AKT and ERK pathways-dependent downregulation of MMP-9 expression. This study also provides a previously neglected insight into the investigation of plant-derived agents-based therapy against tumor invasion with the consideration of damage to healthy cells.