BACKGROUND Nobiletin (N), a polymethoxylated flavone from citrus fruits, enhanced anti-cancer effects of paclitaxel (PTX) in multi-drug resistance (MDR) cancer cells via inhibiting P-glycoprotein (P-gp) in our previous report. But the in vivo chemo-sensitizing effect of nobiletin is unknown. Moreover, considering the nonlinear pharmacokinetics and narrow therapeutic window of PTX, drug-drug interaction should be explored for using nobiletin with PTX together. PURPOSE In this study, we wanted to explore whether nobiletin could affect the pharmacokinetic (PK) behavior of PTX and reverse drug resistance in vivo as well as the corresponding mechanisms. STUDY DESIGN AND METHODS Accurate and sensitive UPLC-MS/MS method was developed for the detection of PTX, and was applied to the pharmacokinetic study in rats. In vivo anti-MDR tumor study was carried out with A549/T xenograft nude mice model. Immunohistochemistry and western blot analysis were used for evaluating the levels of P-gp, Nrf2, and AKT/ERK pathways in MDR tumors. RESULTS Nobiletin significantly enhanced the therapeutic effects of PTX, and inhibited the MDR tumor sizes in the A549/T xenograft model, while PTX or nobiletin alone did not. We found that nobiletin increased the PTX concentrations in tumor tissues but did not affect the PK behavior of PTX. Notably, Nrf2 and phosphorylation of AKT/ERK expression in MDR tumor tissues were significantly inhibited by giving nobiletin and PTX together. However, nobiletin did not affect the expression of P-gp. CONCLUSION Nobiletin reversed PTX resistance in MDR tumor via increasing the PTX content in the MDR tumor and inhibiting AKT/ERK/Nrf2 pathways, but without affecting the systematic exposure of PTX, indicating that nobiletin may be an effective and safe MDR tumor reversal agent.

中文翻译：

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Nobiletin在A549 / T异种移植模型中增强紫杉醇的抗癌功效：药代动力学和药理学研究。

背景技术在我们以前的报道中，来自柑橘类水果的聚甲氧基黄酮Nobiletin（N）通过抑制P-糖蛋白（P-gp）增强了紫杉醇（PTX）在多药耐药（MDR）癌细胞中的抗癌作用。但是，nobiletin在体内的化学致敏作用尚不清楚。此外，考虑到PTX的非线性药代动力学和狭窄的治疗窗口，应探索将诺比列汀与PTX一起使用的药物相互作用。目的在这项研究中，我们想探讨诺比列汀是否会影响PTX的药代动力学（PK）行为和体内逆转耐药性以及相应的机制。研究设计与方法开发了准确灵敏的UPLC-MS / MS方法检测PTX，并将其应用于大鼠的药代动力学研究。用A549 / T异种移植裸鼠模型进行体内抗MDR肿瘤研究。免疫组织化学和蛋白质印迹分析用于评估MDR肿瘤中P-gp，Nrf2和AKT / ERK途径的水平。结果Nobiletin在A549 / T异种移植模型中显着增强了PTX的治疗效果，并抑制了MDR肿瘤的大小，而单独使用PTX或nobiletin则没有。我们发现，nobiletin增加了肿瘤组织中PTX的浓度，但没有影响PTX的PK行为。值得注意的是，诺贝列汀和PTX一起给予可显着抑制MDR肿瘤组织中的Nrf2和AKT / ERK表达的磷酸化。然而，诺比列汀不影响P-gp的表达。结论Nobiletin通过增加MDR肿瘤中的PTX含量并抑制AKT / ERK / Nrf2途径来逆转MDR肿瘤中的PTX耐药性，