Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
Phytomedicine. 2013 Feb 15;20(3-4):282-94. doi: 10.1016/j.phymed.2012.11.005. Epub 2012 Dec 11.
Cancer cells often develop multidrug resistance (MDR) which is a multidimensional problem involving several mechanisms and targets. This study demonstrates that chelidonine and an alkaloid extract from Chelidonium majus, which contains protoberberine and benzo[c]phenanthridine alkaloids, has the ability to overcome MDR of different cancer cell lines through interaction with ABC-transporters, CYP3A4 and GST, by induction of apoptosis, and cytotoxic effects. Chelidonine and the alkaloid extract inhibited P-gp/MDR1 activity in a concentration-dependent manner in Caco-2 and CEM/ADR5000 and reversed their doxorubicin resistance. In addition, chelidonine and the alkaloid extract inhibited the activity of the drug modifying enzymes CYP3A4 and GST in a dose-dependent manner. The alkaloids induced apoptosis in MDR cells which was accompanied by an activation of caspase-3, -8,-6/9, and phosphatidyl serine (PS) exposure. cDNA arrays were applied to identify differentially expressed genes after treatment with chelidonine and the alkaloid extract. The expression analysis identified a common set of regulated genes related to apoptosis, cell cycle, and drug metabolism. Treatment of Caco-2 cells with 50 μg/ml alkaloid extract and 50 μM chelidonine for up to 48 h resulted in a significant decrease in mRNA levels of P-gp/MDR1, MRP1, BCRP, CYP3A4, GST, and hPXR and in a significant increase in caspase-3 and caspase-8 mRNA. Thus, chelidonine is a promising model compound for overcoming MDR and for enhancing cytotoxicity of chemotherapeutics, especially against leukaemia cells. Its efficacy needs to be confirmed in animal models.
癌细胞常发生多药耐药（MDR），这是一个涉及多个机制和靶点的多维问题。本研究表明，白屈菜碱和白屈菜中的一种生物碱提取物，其中含有原小檗碱和苯并[c]菲啶生物碱，通过与 ABC 转运蛋白、CYP3A4 和 GST 相互作用，诱导细胞凋亡和细胞毒性作用，具有克服不同癌细胞系 MDR 的能力。白屈菜碱和生物碱提取物以浓度依赖的方式抑制 Caco-2 和 CEM/ADR5000 中的 P-糖蛋白/MDR1 活性，并逆转其多柔比星耐药性。此外，白屈菜碱和生物碱提取物以剂量依赖的方式抑制药物修饰酶 CYP3A4 和 GST 的活性。生物碱在 MDR 细胞中诱导细胞凋亡，同时激活 caspase-3、-8、-6/9 和磷脂酰丝氨酸（PS）暴露。应用 cDNA 阵列鉴定用白屈菜碱和生物碱提取物处理后差异表达的基因。表达分析鉴定了一组与细胞凋亡、细胞周期和药物代谢相关的差异表达基因。用 50μg/ml 生物碱提取物和 50μM 白屈菜碱处理 Caco-2 细胞长达 48 小时，导致 P-糖蛋白/MDR1、MRP1、BCRP、CYP3A4、GST 和 hPXR 的 mRNA 水平显著降低，caspase-3 和 caspase-8 的 mRNA 水平显著增加。因此，白屈菜碱是克服 MDR 和增强化疗药物细胞毒性的有前途的模型化合物，特别是针对白血病细胞。其疗效需要在动物模型中得到证实。
