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2016年7月16日，英国泰勒与弗朗西斯出版集团旗下《癌症生物学与治疗》杂志在线发表的研究报告，发现小檗碱（黄连素）通过提高活性氧类（氧自由基）水平，可逆转HER2阳性乳腺癌细胞对拉帕替尼耐药。 拉帕替尼是一种用于治疗HER2阳性乳腺癌的新型HER2/EGFR酪氨酸激酶抑制剂。然而，获得性耐药限制了拉帕替尼的临床疗效。既往研究发现，抑制自噬可减少拉帕替尼耐药细胞的增殖、DNA合成和集落形成能力。由于小檗碱（黄连素）在乳腺癌治疗中广泛的生化和药理作用，已被广为关注。根据既往报道，小檗碱（黄连素）在人乳腺癌细胞中可诱导氧化应激和线粒体相关凋亡通路。 该研究发现小檗碱（黄连素）与拉帕替尼的新联合疗法克服了拉帕替尼耐药。此外，该研究还发现小檗碱（黄连素）通过上调活性氧类（氧自由基）水平以诱导拉帕替尼耐药细胞凋亡，拉帕替尼激活耐药细胞中的c-Myc/pro-Nrf2通路和GSK-3β信号转导以稳定Nrf2并保持活性氧类（氧自由基）低水平，小檗碱（黄连素）通过下调c-Myc可扰乱活性氧类（氧自由基）平衡以扭转拉帕替尼耐药。 因此，该研究结果提供了一种使用小檗碱（黄连素）克服拉帕替尼耐药的新策略。 基金项目：国家自然科学基金（81202091，81372390，81402186）。 Cancer Biol Ther. 2016 Jul 14. [Epub ahead of print] Berberine reverses lapatinib resistance of HER2-positive breast cancer cells by increasing the level of ROS. Zhang R, Qiao H, Chen S, Chen X, Dou K, Li W, Zhang J. The Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Lapatinib, a novel tyrosine kinase inhibitor of HER2/EGFR, is used to treat HER2-positive breast cancer. However, acquired drug resistance has limited the clinical therapeutic efficacy of lapatinib. Our previous study found that inhibition of autophagy can reduce the proliferation, DNA synthesis, and colony-forming capacity of lapatinib-resistant cells. Berberine has attracted extensive attention due to its wide range of biochemical and pharmacological effects in breast cancer treatment. It has been reported that berberine can induce oxidative stress and the mitochondrial-related apoptotic pathway in human breast cancer cells. In our current study, we found that a new combination therapy of berberine with lapatinib overcame lapatinib resistance. Furthermore, we found that berberine induced apoptosis of lapatinib-resistant cells through upregulating the level of ROS. Specially, lapatinib activated both the c-Myc/pro-Nrf2 pathway and GSK-3β signaling to stabilize Nrf2 and maintain a low level of ROS in resistant cells. However, berberine can upset the ROS balance by downregulating c-Myc to reverse the lapatinib resistance. Our finding provides a novel strategy of using berberine to overcome lapatinib resistance. KEYWORDS: Berberine; Drug resistance; GSK-3β; Lapatinib; Nrf2,c-Myc; ROS PMID: 27416292 DOI: 10.1080/15384047.2016.1210728 |
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