Department of Applied Biology, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
Department of Applied Biology, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China; ECUST-FONOW Joint Research Center for Innovative Medicines, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
Toxicon. 2023 Jun 15;229:107129. doi: 10.1016/j.toxicon.2023.107129. Epub 2023 Apr 20.
Plant-derived triterpenoid saponins have been shown to play a powerful role in enhancing the cytotoxic activity of protein therapeutics. However, the mechanism of how saponins are acting is not clearly understood. In this study, momordin Ic (MIC), a triterpenoid saponin derived from Kochia scoparia (L.) Schrad., specifically enhance the antiproliferative effect of recombinant MAP30 (a type I ribosome inactivating protein, RIP) in breast cancer cells. Subsequently, the possible mechanism of how MIC enhanced the cytotoxicity of MAP30 was analyzed in detail. We observed the level of intracellular labeled MAP30 using fluorescence microscopy and flow cytometry. And a reporter protein, GAL9, was used to monitor the role of MIC in promoting endosomal escape. We found endosomal escape does not play a role for the enhancer effect of MIC while the effect of MIC on MAP30 is cholesterol dependent and that ganglioside GM1, a lipid raft marker, can competitively inhibit cytotoxicity of MAP30 enhanced by MIC. Finally, we provided some insights into the correlation between the sugar side chain of MIC and its role in enhancing of RIP cytotoxicity and altering of drug cell tropism.
植物来源的三萜皂苷已被证明在增强蛋白治疗药物的细胞毒性活性方面发挥着强大的作用。然而，皂苷的作用机制尚不清楚。在这项研究中，苦参中的苦参碱 Ic（MIC），一种从苦参（L.）Schrad. 中提取的三萜皂苷，可特异性增强重组 MAP30（一种 I 型核糖体失活蛋白，RIP）在乳腺癌细胞中的抗增殖作用。随后，详细分析了 MIC 增强 MAP30 细胞毒性的可能机制。我们使用荧光显微镜和流式细胞术观察细胞内标记 MAP30 的水平。并使用报告蛋白 GAL9 来监测 MIC 在促进内体逃逸中的作用。我们发现内体逃逸对 MIC 的增强作用不起作用，而 MIC 对 MAP30 的作用是胆固醇依赖性的，神经节苷脂 GM1，一种脂筏标记物，可竞争性抑制 MIC 增强的 MAP30 的细胞毒性。最后，我们深入探讨了 MIC 的糖侧链与其在增强 RIP 细胞毒性和改变药物细胞趋向性方面的作用之间的相关性。
