Laboratory of Chemical Genomics, Korea Research Institute of Chemical Technology, Daejeon, Korea.
Phytother Res. 2010 Jul;24(7):1042-6. doi: 10.1002/ptr.3073.
In this study, we evaluated whether euphorbiasteroid isolated from Euphorbia lathyris has the potential to reverse P-glycoprotein (P-gp)-mediated multi-drug resistance (MDR) by using the drug-sensitive human sarcoma cell line MES-SA and its MDR counterpart MES-SA/Dx5. Interestingly, even at low concentrations of euphorbiasteroid (1-3 microM), it efficiently restored the toxicities of anticancer drugs including vinblastine, taxol and doxorubicin in MES-SA/Dx5 cells. Additionally, the computational Bayesian model for predicting potential P-gp substrates or inhibitors revealed that euphorbiasteroid showed 97% probability for substrate likeness having similar molecular features with 50 P-gp substrates. Consistent with this result, the substrate likeness of euphorbiasteroid was also experimentally confirmed by P-gp ATPase activity assay. In conclusion, our finding suggested that euphorbiasteroid could be a transport substrate for P-gp that can effectively inhibit P-gp-mediated drug transport and reverse resistance to anticancer drugs in MES-SA/Dx5 cells.
在这项研究中，我们使用对多药耐药（MDR）敏感的人肉瘤细胞系 MES-SA 及其 MDR 对应物 MES-SA/Dx5，评估大戟甾醇是否有逆转 P-糖蛋白（P-gp）介导的多药耐药的潜力。有趣的是，即使在低浓度的大戟甾醇（1-3 μM）下，它也能有效地恢复长春碱、紫杉醇和阿霉素等抗癌药物在 MES-SA/Dx5 细胞中的毒性。此外，用于预测潜在 P-gp 底物或抑制剂的计算贝叶斯模型表明，大戟甾醇具有 97%的底物相似性概率，具有与 50 种 P-gp 底物相似的分子特征。与这一结果一致，P-gp ATP 酶活性测定实验也证实了大戟甾醇的底物相似性。总之，我们的发现表明大戟甾醇可能是 P-gp 的转运底物，能够有效抑制 P-gp 介导的药物转运，并逆转 MES-SA/Dx5 细胞中抗癌药物的耐药性。
