摘要
P-糖蛋白(ABCB1/P-gp)高表达被认为是肿瘤多药耐药(multidrug resistance,MDR)发生的关键因素.因此,发现能有效逆转ABCB1介导肿瘤多药耐药的药物,已成为当务之急.新芒果苷(Neomangiferin)是一种来源于知母的多酚类碳苷化合物,具有抗炎、抗氧化和抗肿瘤的功效.该研究探讨了Neomangiferin能否有效克服ABCB1介导的肿瘤多药耐药及其机制.网络药理学实验结果显示,知母活性成分Neomangiferin与ABCB1关系密切.MTT与平板克隆实验结果表明,Neomangiferin可有效克服ABCB1介导的肿瘤多药耐药(P＜0.05).Western blot及免疫荧光实验结果揭示,Neomangiferin对ABCB1蛋白在细胞内的表达水平和定位没有影响.药物蓄积与外排实验结果表明,Neomangiferin通过抑制ABCB1蛋白的外排作用,增加细胞内化疗药物的蓄积,进而克服肿瘤多药耐药.此外,分子对接与热稳定性实验显示,Neomangiferin能与ABCB1蛋白稳定结合.总之,该研究发现,Neomangiferin能有效克服ABCB1介导的肿瘤多药耐药,为化疗耐药的肿瘤患者带来了一种崭新的治疗策略.
Abstract
The overexpression of P-glycoprotein(ABCB1/P-gp)is a key factor in causing MDR(multi-drug resistance)in cancers.Therefore,it is crucial to discover effective drugs against ABCB1 to overcome MDR.Neomangiferin,a polyphenolic carbonyl glycoside compound derived from Anemarrhenae Rhizoma,has anti-inflammatory,antioxidant and anti-tumor properties.This study investigated whether Neomangiferin could effec-tively overcome ABCB1-mediated MDR and its mechanism.The result of network pharmacology assay showed that Neomangiferin,the active ingredient of Anemarrhenae Rhizoma,was closely related to ABCB1.The results of MTT and colony formation assays indicated that Neomangiferin could effectively overcome ABCB 1-mediated MDR(P＜0.05).The results of Western blot and immunofluorescence revealed that Neomangiferin had no effect on the expression and localization of ABCB1 protein in cells.The results of drug accumulation and efflux experiments showed that Neomangiferin increased the intracellular accumulation of chemotherapeutic drugs by inhibiting the efflux of ABCB1 protein,thus overcoming MDR.In addition,molecular docking and thermal stability experiments showed that Neomangiferin could stably bind to ABCB1 protein.In conclusion,this study found that Neomangif-erin could effectively overcome ABCB1-mediated MDR,providing a novel therapeutic strategy for chemotherapy-resistant tumor patients.
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