PDF(Pubmed)
Abstract：
Multidrug resistance (MDR) remains the most difficult problem facing conventional chemotherapy for cancers. Astragalus membranaceus is a historically traditional Chinese medicine. One of its bioactive components, formononetin, exhibits antitumor effects on various cancers. However, the effects of formononetin on MDR cancers have not been evaluated. Therefore, we investigated the defense\'s effects of formononetin on MDR. We used rhodamine 123 and doxorubicin efflux assays to analyze the inhibition kinetics of P-glycoprotein (P-gp) mediated-efflux. Cell viability was detected by sulforhodamine B assay, and the synergistic effects of formononetin combined with chemotherapeutic agents were further calculated using CompuSyn software. Molecular docking was performed with iGEMDOCK. We discovered that formononetin considerably induced oxidative stress and the disruption of mitochondrial membrane potential in MDR cancer cells. Furthermore, formononetin inhibits the P-gp efflux function by ATPase stimulation and the uncompetitive inhibition of P-gp-mediated effluxes of rhodamine 123 and doxorubicin. The molecular docking model indicates that formononetin may bind to P-gp by strong hydrogen bonds at Arginine (Arg) 489 and Glutamine (Gln) 912. Formononetin exhibits significant synergistic effects with vincristine and doxorubicin toward MDR cancer cells, and it synergistically suppressed tumor growth in vivo with paclitaxel. These results suggest that formononetin should be seen as a potential candidate for the adjuvant therapy of MDR cancers.
摘要：
多药耐药（MDR）仍然是癌症常规化疗面临的最困难的问题。黄芪是一种历史悠久的中药。它的生物活性成分之一，福蒙素,对各种癌症具有抗肿瘤作用。然而,目前还没有评价芒诺酮对MDR癌症的作用.因此,我们研究了海蒙素对MDR的防御作用。我们使用罗丹明123和阿霉素外排测定法来分析P-糖蛋白（P-gp）介导的外排的抑制动力学。通过磺罗丹明B测定法检测细胞活力，并使用CompuSyn软件进一步计算了海蒙素与化疗药物的协同作用。用IGEMDOCK进行分子对接。我们发现，在MDR癌细胞中，formononetin可显著诱导氧化应激和线粒体膜电位的破坏。此外，通过ATPase刺激和P-gp介导的罗丹明123和阿霉素的非竞争性抑制来抑制P-gp外排功能。分子对接模型表明，在精氨酸（Arg）489和谷氨酰胺（Gln）912上，通过强氢键与P-gp结合。Formononetin与长春新碱和多柔比星对MDR癌细胞具有显著的协同作用，它与紫杉醇协同抑制体内肿瘤生长。这些结果表明，应将Formononetin视为MDR癌症辅助治疗的潜在候选者。
