Multidrug resistance (MDR) is one of the main reasons affecting the efficacy of chemotherapy in breast cancer (BC). Our previous studies constructed polymer lipid hybrid nanoparticles encapsulated with Emodin (EMO) (E-PLNs) and proved that they can inhibit epithelial mesenchymal transition (EMT) and reverse MDR in BC. This study aims to explore the mechanisms by which the EMT involved in MDR and the E-PLNs exerted effects. The prepared E-PLNs were characterized by Dynamic light scattering, infrared spectroscopy, X-ray, and differential scanning calorimetry. The effects of drugs or treatments were evaluated by detecting cell viability, apoptosis, invasion, EMT markers, and MDR related proteins in vitro. The results showed that IL-6 could promote proliferation, EMT, invasion and MDR of MCF-7/ADR cells (induced from MCF-7 cells) by activating the JAK2/STAT3 signaling pathway, and these effects could be reversed by AG490 (JAK2 inhibitor) or E-PLNs combined with Doxorubicin (DOX). E-PLNs might be an effective MDR reversal agent for BC. Polymer lipid hybrid nanoparticles encapsulated with Emodin had good physical and chemical properties, improving the bioavailability and efficacy of Emodin. Compared with parental MCF-7 cells, MCF-7/ADR cells overexpressed markers of epithelial mesenchymal transition (EMT), and Galunisertib (EMT inhibitor) inhibited EMT and reversed MDR. Compared with parental MCF-7 cells, MCF-7/ADR cells secreted high level of IL-6. Exogenous IL-6 promoted proliferation, invasion, EMT, and MDR of MCF-7/ADR cells by activating the JAK2/STAT3 pathway. AG490 (JAK2 inhibitor) and/or E-PLNs combined with DOX downregulated the IL-6/JAK2/STAT3 pathway and inhibited its mediated proliferation, invasion, EMT, and MDR in MCF-7/ADR cells.

中文翻译：

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大黄素包裹的聚合物脂质杂化纳米粒联合DOX通过IL-6/JAK2/STAT3信号通路逆转乳腺癌多药耐药

多药耐药（MDR）是影响乳腺癌（BC）化疗疗效的主要原因之一。我们前期的研究构建了包裹有大黄素（EMO）（E-PLNs）的聚合物脂质杂化纳米颗粒，并证明它们可以抑制上皮间质转化（EMT）并逆转BC中的MDR。本研究旨在探讨参与MDR的EMT和E-PLNs发挥作用的机制。通过动态光散射、红外光谱、X 射线和差示扫描量热法对制备的 E-PLN 进行了表征。通过体外检测细胞活力、凋亡、侵袭、EMT 标志物和 MDR 相关蛋白来评估药物或治疗的效果。结果表明，IL-6可以通过激活JAK2/STAT3信号通路促进MCF-7/ADR细胞（由MCF-7细胞诱导）的增殖、EMT、侵袭和MDR，并且这些作用可以被AG490（JAK2）逆转。抑制剂）或 E-PLN 与阿霉素 (DOX) 联合。E-PLN 可能是 BC 的有效 MDR 逆转剂。大黄素包裹的聚合物脂质杂化纳米粒具有良好的理化性质，提高了大黄素的生物利用度和药效。与亲代MCF-7细胞相比，MCF-7/ADR细胞过度表达上皮间质转化（EMT）标志物，而Galunisertib（EMT抑制剂）可抑制EMT并逆转MDR。与亲本MCF-7细胞相比，MCF-7/ADR细胞分泌高水平的IL-6。外源性IL-6通过激活JAK2/STAT3通路促进MCF-7/ADR细胞的增殖、侵袭、EMT和MDR。AG490（JAK2抑制剂）和/或E-PLNs与DOX联合下调IL-6/JAK2/STAT3通路并抑制其介导的MCF-7/ADR细胞的增殖、侵袭、EMT和MDR。