Feng Sen-Ling, Luo Hai-Bin, Cai Liang, Zhang Jie, Wang Dan, Chen Ying-Jiang, Zhan Huan-Xing, Jiang Zhi-Hong, Xie Ying
State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
School of Pharmaceutical Science, Sun Yat-sen University, China.
J Ginseng Res. 2020 Mar;44(2):247-257. doi: 10.1016/j.jgr.2018.10.007. Epub 2018 Nov 8.
Multidrug resistance (MDR) to chemotherapy drugs remains a major challenge in clinical cancer treatment. Here we investigated whether and how ginsenoside Rg5 overcomes the MDR mediated by ABCB1 transporter and .
Cytotoxicity and colon formation as well as the intracellular accumulation of ABCB1 substrates were carried out in MDR cancer cells A2780/T and A549/T for evaluating the reversal effects of Rg5. The expressions of ABCB1 and Nrf2/AKT pathway were determined by Western blotting. An A549/T cell xenograft model was established to investigate the MDR reversal activity of Rg5 .
Rg5 significantly reversed ABCB1-mediated MDR by increasing the intracellular accumulation of ABCB1 substrates without altering protein expression of ABCB1. Moreover, Rg5 activated ABCB1 ATPase and reduced verapamil-stimulated ATPase activity, suggesting a high affinity of Rg5 to ABCB1 binding site which was further demonstrated by molecular docking analysis. In addition, co-treatment of Rg5 and docetaxel (TXT) suppressed the expression of Nrf2 and phosphorylation of AKT, indicating that sensitizing effect of Rg5 associated with AKT/Nrf2 pathway. In nude mice bearing A549/T tumor, Rg5 and TXT treatment significantly suppressed the growth of drug-resistant tumors without increase in toxicity when compared to TXT given alone at same dose.
Therefore, combination therapy of Rg5 and chemotherapy drugs is a strategy for the adjuvant chemotherapy, which encourages further pharmacokinetic and clinical studies.
化疗药物的多药耐药性（MDR）仍然是临床癌症治疗中的一个主要挑战。在此，我们研究了人参皂苷Rg5是否以及如何克服由ABCB1转运蛋白介导的多药耐药性。
在多药耐药癌细胞A2780/T和A549/T中进行细胞毒性、集落形成以及ABCB1底物的细胞内积累实验，以评估Rg5的逆转作用。通过蛋白质印迹法测定ABCB1和Nrf2/AKT信号通路的表达。建立A549/T细胞异种移植模型，以研究Rg5的多药耐药逆转活性。
Rg5通过增加ABCB1底物的细胞内积累显著逆转了ABCB1介导的多药耐药性，而不改变ABCB1的蛋白质表达。此外，Rg5激活了ABCB1 ATP酶并降低了维拉帕米刺激的ATP酶活性，表明Rg5对ABCB1结合位点具有高亲和力，分子对接分析进一步证实了这一点。此外，Rg5和多西他赛（TXT）联合处理抑制了Nrf2的表达和AKT的磷酸化，表明Rg5的增敏作用与AKT/Nrf2信号通路有关。在携带A549/T肿瘤的裸鼠中，与相同剂量单独给予TXT相比，Rg5和TXT联合治疗显著抑制了耐药肿瘤的生长，且未增加毒性。
因此，Rg5与化疗药物联合治疗是辅助化疗的一种策略，这鼓励进一步开展药代动力学和临床研究。
