AbMole 小讲堂丨Artemisinin：青蒿素在氧化应激与铁代谢研究中的应用

Artemisinin青蒿素AbMoleM4382是从黄花蒿中提取的倍半萜内酯类化合物其分子结构中的过氧桥键–O–O–是发挥生物活性的核心基团[1]。ArtemisininCAS No.63968-64-9进入细胞后Fe²⁺催化过氧桥键裂解产生大量碳中心自由基和活性氧ROS引发脂质过氧化、蛋白氧化损伤、线粒体功能障碍及铁死亡。疟原虫在血红素降解过程中释放大量游离Fe²⁺这一独特的铁代谢特征使Artemisinin青蒿素对疟原虫表现出高度选择性毒性[1]。近年来Artemisinin青蒿素的铁依赖性细胞毒机制被拓展至肿瘤研究领域——肿瘤细胞因快速增殖而维持较高的细胞内游离铁水平为Artemisinin的激活提供了有利条件。在细胞实验层面Artemisinin青蒿素AbMoleM4382的活性呈现显著的铁依赖性特征。在K562白血病细胞中50 μM的Artemisinin处理24小时可诱导剂量依赖性细胞死亡且与FeCl2或转铁蛋白联合使用时细胞毒效应显著增强Artemisinin在HeLa宫颈癌细胞中25–100 μM能抑制细胞增殖并诱导G0/G1期阻滞同时上调HO-1等抗氧化应激基因的表达[2]。类似的在HepG2肝癌细胞中50 μM Artemisinin能通过激活线粒体凋亡通路降低细胞存活率且该效应可被铁螯合剂去铁胺DFO部分逆转[3]。在动物实验层面ArtemisininCAS No.63968-64-9在小鼠疟原虫感染模型中通过灌胃给药100 mg/kg每日一次连续3–5天可显著降低原虫血症并延长生存期在大鼠肿瘤移植模型中腹腔注射50–150 mg/kg隔日一次可抑制肿瘤生长并降低组织铁含量[4]。Artemisinin青蒿素AbMoleM4382还被用于探索其在神经退行性疾病模型中的神经保护作用其机制涉及抑制NF-κB信号通路及减轻小胶质细胞活化[5]。参考文献及鸣谢[1] Meshnick, S. R.; Taylor, T. E.; Kamchonwongpaisan, S. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiological Reviews 1996, 60 (2), 301–315.[2] Efferth, T.; Dunstan, H.; Sauerbrey, A.; et al. The anti-malarial artesunate is also active against cancer. International Journal of Oncology 2001, 18 (4), 767–773.[3] Lai, H.; Singh, N. P. Oral artemisinin prevents and delays the development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in the rat. Cancer Letters 2006, 231 (1), 43–48.[4] Li, Y.; Shan, F.; Shang, Y.; et al. Enhancing the activities of artemisinin against breast cancer cells via induced apoptosis and cell cycle arrest by a polymeric nanocarrier. RSC Advances 2016, 6 (65), 60022–60033.[5] Ferreira, J. F. S.; Luthria, D. L.; Sasaki, T.; et al. Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer. Molecules 2010, 15 (5), 3135–3170.