■非小细胞肺癌(NSCLC)是最常见的恶性肿瘤之一,化疗仍然是晚期的主要治疗方法。然而,ABC结合盒转运蛋白的高表达,包括MRP,P-GP,LRP,以及多药耐药蛋白,已被确定为导致化疗药物敏感性降低的重要因素。本研究旨在探讨Curculitinisrhizoma[低氧科;CurculigoorchioidesGaertn的影响和潜在机制。](CR)联合顺铂改善ABC结合盒转运蛋白和多药耐药蛋白介导的NSCLC化疗耐药。
■为了解开JNK之间的关系,MRP,P-GP,和LRP在非小细胞肺癌中的作用,并深入了解CR的调控机制,这项研究采用了包含生物信息学的综合方法,分子对接,分子动力学,动物和细胞实验。生物信息学分析显示JNK的表达水平显着增加,MRP,P-GP,多药耐药非小细胞肺癌的LRP亚型。随后的动物实验表明,CR与顺铂的组合可以提高肺癌小鼠的生存率。分子对接和分子动力学分析证明了仙茅苷与上述JNK亚型之间的有利结合相互作用,MRP,P-GP,LRP。在细胞实验中,顺铂与姜黄苷和CR提取物的组合导致细胞活力的显着降低和JNK1,JNK2,MRP1,MRP2,MRP4,P-gp的表达下调,和LRP1在A549/顺式细胞中。
■值得注意的是,姜黄苷对JNK1、MRP1、MRP2、MRP4和LRP1的表达水平具有显著的下调作用。CR,特别是其主要有效代谢产物,Curculigoside,有可能通过调节JNK/MRP/LRP/P-gp的水平和减轻多药耐药来增强非小细胞肺癌对顺铂的敏感性。
UNASSIGNED: Non-small cell lung cancer (NSCLC) stands as one of the most prevalent malignancies, and chemotherapy remains the primary treatment for advanced stages. However, the high expression of ABC binding cassette transporters, including MRP, P-gp, and LRP, along with multidrug resistance proteins, has been identified as a significant factor contributing to decreased chemotherapy drug sensitivity. This study aims to explore the impact and underlying mechanisms of Curculiginis Rhizoma [Hypoxidaceae; Curculigo orchioides Gaertn.] (CR) in combination with cisplatin on improving chemoresistance mediated by ABC binding cassette transporters and multidrug resistance proteins in NSCLC.
UNASSIGNED: To unravel the relationship between JNK, MRP, P-gp, and LRP in NSCLC and gain insights into the regulatory mechanism of CR, this study employs an integrated approach encompassing bioinformatics, molecular docking, molecular dynamics, animal and cellular experiments. Bioinformatics analysis revealed a significant increase in the expression levels of JNK, MRP, P-gp, and LRP subtypes in multidrug-resistant non-small cell lung cancer. Subsequent animal experiments have shown that the combination of CR with cisplatin can improve the survival rate of lung cancer mice. Molecular docking and molecular dynamics analyses demonstrated favorable binding interactions between curculigoside and the aforementioned subtypes of JNK, MRP, P-gp, and LRP. In cellular experiments, the combination of cisplatin with both curculigoside and CR extract resulted in a notable decrease in cell viability and downregulation of the expression of JNK1, JNK2, MRP1, MRP2, MRP4, P-gp, and LRP1 in A549/cis cells.
UNASSIGNED: Remarkably, curculigoside exerted a significant downregulation effect on the expression levels of JNK1, MRP1, MRP2, MRP4, and LRP1. CR, particularly its main effective metabolite, curculigoside, has the potential to enhance the sensitivity of non-small cell lung cancer to cisplatin by regulating levels of JNK/MRP/LRP/P-gp and mitigating multidrug resistance.