简介：胶质母细胞瘤每年影响大量患者，诊断后平均总寿命约为 14.6 个月，是最致命的原发性侵袭性脑肿瘤。目前，手术、放疗和替莫唑胺（TMZ）化疗是临床三大主要治疗手段。然而，有效治疗患者的能力通常受到 TMZ 耐药性的限制。柚皮苷是一种具有抗癌、抗氧化、金属螯合和降脂作用的生物类黄酮，已成为一种有前途的治疗选择。方法：采用基于细胞系的 ELISA、流式细胞术、免疫细胞化学、蛋白质印迹和基于 LC-HRMS 的代谢组学研究，探讨柚皮苷和 TMZ 在胶质母细胞瘤网络药理学中的靶点和通路。结果：网络药理学结果表明柚皮苷对胶质母细胞瘤化疗增敏的关键靶点是聚[ADP-核糖]聚合酶1（PARP-1）、O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）和半胱天冬酶。功能富集分析表明，这些靶标在 p53 信号传导、细胞凋亡和 DNA 传感等重要通路中显着富集。此外，U87-MG 和 T98-G 胶质母细胞瘤细胞的体外研究结果表明，TMZ 和柚皮苷一起显着降低活力百分比，并抑制 DNA 修复酶 PARP-1 和 MGMT 以及 PI3K/AKT，从而导致细胞凋亡。 p53、caspase-3 表达增加和 Bcl2 表达减少表明细胞凋亡。此外，使用液相色谱高分辨率质谱 (LC-HRMS) 对 T98-G 胶质母细胞瘤细胞进行的代谢组学研究显示，C8-肉碱 (-2.79)、L-己酰肉碱 (-4.46)、DL-肉碱 (-2.46) 下调、乙酰基-L-肉碱 (-3.12)、腺嘌呤 (-1.3)、胆碱 (-2.07)、丙酰肉碱 (-1.69)、肌酸 (-1.33)、腺苷 (-0.84)、精胺 (-1.42) 和上调柚皮苷和 TMZ 治疗组中的棕榈酸 (1.03) 和鞘氨醇 (0.89)。讨论：总之，可以说柚皮苷与 TMZ 联合使用可增强 TMZ 抗神经胶质瘤反应并诱导肿瘤细胞凋亡。版权所有 © 2024 Bisht、Prasad、Choudhary、Pandey、Aishwarya、Aravind、Ramalingam、Velayutham 和 Kumar。

Introduction: Glioblastoma, which affects a large number of patients every year and has an average overall lifespan of around 14.6 months following diagnosis stands out as the most lethal primary invasive brain tumor. Currently, surgery, radiation, and chemotherapy with temozolomide (TMZ) are the three major clinical treatment approaches. However, the ability to treat patients effectively is usually limited by TMZ resistance. Naringin, a bioflavonoid with anti-cancer, antioxidant, metal-chelating, and lipid-lowering effects, has emerged as a promising therapeutic option. Methods: To explore the targets and pathways of naringin and TMZ in glioblastoma network pharmacology, cell line-based ELISA, flow cytometry, immunocytochemistry, western blotting, and LC-HRMS based metabolomics study were used. Results: The findings through the network pharmacology suggested that the key targets of naringin in the chemosensitization of glioblastoma would be Poly [ADP-ribose] polymerase 1 (PARP-1), O-6-Methylguanine-DNA Methyltransferase (MGMT), and caspases. The functional enrichment analysis revealed that these targets were significantly enriched in important pathways such as p53 signaling, apoptosis, and DNA sensing. Further, the results of the in-vitro study in U87-MG and T98-G glioblastoma cells demonstrated that TMZ and naringin together significantly reduced the percentage of viability and inhibited the DNA repair enzymes PARP-1 and MGMT, and PI3K/AKT which led to chemosensitization and, in turn, induced apoptosis, which was indicated by increased p53, caspase-3 expression and decreased Bcl2 expression. Additionally, a metabolomics study in T98-G glioblastoma cells using liquid chromatography high-resolution mass spectrometry (LC-HRMS) revealed downregulation of C8-Carnitine (-2.79), L-Hexanoylcarnitine (-4.46), DL-Carnitine (-2.46), Acetyl-L-carnitine (-3.12), Adenine (-1.3), Choline (-2.07), Propionylcarnitine (-1.69), Creatine (-1.33), Adenosine (-0.84), Spermine (-1.42), and upregulation of Palmitic Acid (+1.03) and Sphingosine (+0.89) in the naringin and TMZ treatment groups. Discussion: In conclusion, it can be said that naringin in combination with TMZ chemosensitized TMZ antiglioma response and induced apoptosis in tumor cells.Copyright © 2024 Bisht, Prasad, Choudhary, Pandey, Aishwarya, Aravind, Ramalingam, Velayutham and Kumar.