简介:胶质母细胞瘤,每年影响大量患者,诊断后的平均总体寿命约为14.6个月,是最致命的原发性侵袭性脑肿瘤。目前,手术,辐射,替莫唑胺(TMZ)是三种主要的临床治疗方法。然而,有效治疗患者的能力通常受到TMZ耐药的限制.柚林宁,一种抗癌的生物类黄酮,抗氧化剂,金属螯合,和降脂作用,已经成为一种有希望的治疗选择。方法:探讨柚皮苷和TMZ在胶质母细胞瘤网络药理学中的作用靶点和通路,基于细胞系的ELISA,流式细胞术,免疫细胞化学,西方印迹,和基于LC-HRMS的代谢组学研究。结果:通过网络药理学发现,柚皮苷在胶质母细胞瘤化学致敏中的关键靶标是聚[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。功能富集分析显示,这些靶标在重要的通路如p53信号中显著富集,凋亡,和DNA传感。Further,在U87-MG和T98-G胶质母细胞瘤细胞中的体外研究结果表明,TMZ和柚皮苷一起显着降低了活力百分比并抑制了DNA修复酶PARP-1和MGMT,和PI3K/AKT导致化学敏化,反过来,诱导细胞凋亡,p53,caspase-3表达增加,Bcl2表达降低。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揭示了C8-肉碱(-2.79)的下调,L-己酰基肉碱(-4.46),DL-肉碱(-2.46),乙酰-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),柚皮苷和TMZ治疗组中棕榈酸(+1.03)和鞘氨醇(+0.89)的上调。讨论:总之,可以说柚皮苷与TMZ联合化疗致敏TMZ的抗胶质瘤反应并诱导肿瘤细胞凋亡。
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.