Isoliensinine induces apoptosis in triple-negative human breast cancer cells through ROS generation and p38 MAPK/JNK activation.
Isoliensinine induces apoptosis in triple-negative human breast cancer cells through ROS generation and p38 MAPK/JNK activation.
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Isoliensinine 通过 ROS 生成和 p38 MAPK/JNK 激活诱导三阴性人乳腺癌细胞凋亡。
DOI：
10.1038/srep12579
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发表时间：
2015-07-29
影响因子：
4.6
通讯作者：
Shao C
中科院分区：
文献类型：
--
作者：
Zhang X;Wang X;Wu T;Li B;Liu T;Wang R;Liu Q;Liu Z;Gong Y;Shao C
异莲心碱、莲心碱和莲心碱是莲 (Nelumbo nucifera) 种子胚中的主要双苄基异喹啉生物碱，具有潜在的抗癌活性。在这里，我们探讨了这些生物碱对三阴性乳腺癌细胞的影响，发现三种生物碱中异莲心碱具有最有效的细胞毒性作用，主要是通过诱导细胞凋亡。有趣的是，异莲心碱对正常人乳腺上皮细胞系 MCF-10A 的细胞毒性要低得多。进一步的研究表明，异莲心碱可以显着增加三阴性乳腺癌细胞中活性氧（ROS）的产生，但在MCF-10A细胞中则不然。异莲心碱诱导的细胞凋亡可以被自由基氧清除剂N-乙酰半胱氨酸减弱，这表明异莲心碱对癌细胞的细胞毒作用至少部分是通过诱导氧化应激来实现的。我们发现 p38 MAPK 和 JNK 信号通路均被异莲心碱处理激活，并有助于诱导细胞凋亡。此外，p38 MAPK 和 JNK 的抑制剂或特异性 siRNA 可以减弱异莲心碱诱导的细胞凋亡。然而，只有 p38 抑制剂或 p38 特异性 siRNA 才能阻断异莲心碱处理细胞中 ROS 的升高。因此，我们的研究结果揭示了异莲心碱对乳腺癌细胞具有新的抗肿瘤作用，并可能具有治疗意义。
Isoliensinine, liensinine and neferine are major bisbenzylisoquinoline alkaloids in the seed embryo of lotus (Nelumbo nucifera), and exhibit potential anti-cancer activity. Here, we explored the effects of these alkaloids on triple-negative breast cancer cells and found that among the three alkaloids isoliensinine possesses the most potent cytotoxic effect, primarily by inducing apoptosis. Interestingly, isoliensinine showed a much lower cytotoxicity against MCF-10A, a normal human breast epithelial cell line. Further studies showed that isoliensinine could significantly increase the production of reactive oxygen species (ROS) in triple-negative breast cancer cells, but not in MCF-10A cells. The isoliensinine-induced apoptosis could be attenuated by radical oxygen scavenger N-acetyl cysteine, suggesting that the cytotoxic effect of isoliensinine on cancer cells is at least partially achieved by inducing oxidative stress. We found that both p38 MAPK and JNK signaling pathways were activated by isoliensinine treatment and contributed to the induction of apoptosis. Furthermore, inhibitors or specific siRNAs of p38 MAPK and JNK could attenuate apoptosis induced by isoliensinine. However, only the p38 inhibitor or p38-specific siRNA blocked the elevation of ROS in isoliensinine-treated cells. Our findings thus revealed a novel antitumor effect of isoliensinine on breast cancer cells and may have therapeutic implications.