Poornima Paramasivan, Kumar Velmurugan Bharath, Weng Ching Feng, Padma Viswanadha Vijaya
Animal Tissue Culture and Molecular Genetics Laboratory, Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University, Coimbatore 641046, Tamilnadu, India.
Laboratory of Molecular Physiology, Institute of Biotechnology, Department of Life Sciences, National Dong Hwa University, Hualien 974, Taiwan.
Food Chem Toxicol. 2014 Jun;68:87-98. doi: 10.1016/j.fct.2014.03.008. Epub 2014 Mar 13.
Doxorubicin (DOX) is the best anticancer agent that has ever been used, but acquired tumor resistance and dose limiting toxicity are major road blocks. Concomitant use of natural compounds is a promising strategy to overcome this problem. Neferine, a proven anticancer agent is found in green embryos of lotus seed. The study demonstrates that neferine acts as an effective enhancer of DOX-induced cell death in A549 cells through ROS mediated apoptosis with MAPK activation and inhibition of NF-κB nuclear translocation. Cotreatment of cells with neferine significantly enhanced intracellular DOX-accumulation. Neferine and DOX in combination also triggered oxidative stress through intracellular Ca(2+) accumulation and dissipation of mitochondrial membrane potential in addition to significant loss of cellular antioxidant pool. The MAPK inhibitor effectively decreased the cell-death induced by neferine and DOX. Pretreatment of cells with glutathione reversed the apoptosis induced by combined regimen and recovered the Bcl2/Bax ratio. Moreover, neferine treatment significantly increased the cell viability of DOX-treated cardiomyocytes indicating a possible protective role of neferine towards DOX-induced cardiotoxicity. Taken together, our results suggest that a strategy of using neferine and DOX in combination could be helpful to increase the efficacy of DOX and to achieve anticancer synergism by curbing the toxicity.
阿霉素（DOX）是有史以来使用过的最佳抗癌药物，但获得性肿瘤耐药性和剂量限制性毒性是主要障碍。同时使用天然化合物是克服这一问题的一种有前景的策略。甲基莲心碱是一种已被证实的抗癌剂，存在于莲子的绿色胚芽中。该研究表明，甲基莲心碱通过ROS介导的凋亡、MAPK激活和NF-κB核转位抑制，作为DOX诱导A549细胞死亡的有效增强剂。甲基莲心碱与细胞共同处理可显著增强细胞内DOX的积累。甲基莲心碱和DOX联合使用还通过细胞内Ca(2+)积累和线粒体膜电位耗散引发氧化应激，此外细胞抗氧化池也显著减少。MAPK抑制剂有效降低了甲基莲心碱和DOX诱导的细胞死亡。用谷胱甘肽预处理细胞可逆转联合方案诱导的凋亡并恢复Bcl2/Bax比值。此外，甲基莲心碱处理显著提高了DOX处理的心肌细胞的细胞活力，表明甲基莲心碱对DOX诱导的心脏毒性可能具有保护作用。综上所述，我们的结果表明，联合使用甲基莲心碱和DOX的策略可能有助于提高DOX的疗效，并通过抑制毒性实现抗癌协同作用。
