School of Medicine, Murray Health, Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland SR1 3SD, UK.
School of Human Sciences, London Metropolitan University, Tower Building, Holloway Road, London N7 8DB, UK.
Int J Mol Sci. 2024 Sep 27;25(19):10428. doi: 10.3390/ijms251910428.
Glioblastoma (GBM) is a deadly brain cancer. The prognosis of GBM patients has marginally improved over the last three decades. The response of GBMs to initial treatment is inevitably followed by relapse. Thus, there is an urgent need to identify and develop new therapeutics to target this cancer and improve both patient outcomes and long-term survival. Metabolic reprogramming is considered one of the hallmarks of cancers. However, cell-based studies fail to accurately recapitulate the in vivo tumour microenvironment that influences metabolic signalling and rewiring. Against this backdrop, we conducted global, untargeted metabolomics analysis of the G7 and R24 GBM 2D monolayers and 3D spheroid cultures under identical cell culture conditions. Our studies revealed that the levels of multiple metabolites associated with the vitamin B6 pathway were significantly altered in 3D spheroids compared to the 2D monolayer cultures. Importantly, we show that pharmacological intervention with hydralazine, a small molecule that reduces vitamin B6 levels, resulted in the cell death of 3D GBM spheroid cultures. Thus, our study shows that inhibition of the vitamin B6 pathway is a novel therapeutic strategy for the development of targeted therapies in GBMs.
胶质母细胞瘤（GBM）是一种致命的脑癌。在过去的三十年中，GBM 患者的预后略有改善。GBM 对初始治疗的反应不可避免地会随之复发。因此，迫切需要识别和开发新的治疗方法来靶向这种癌症，并改善患者的预后和长期生存。代谢重编程被认为是癌症的标志之一。然而，基于细胞的研究未能准确再现影响代谢信号和重排的体内肿瘤微环境。在此背景下，我们在相同的细胞培养条件下，对 G7 和 R24 GBM 2D 单层和 3D 球体培养物进行了全局、非靶向代谢组学分析。我们的研究表明，与 2D 单层培养物相比，与维生素 B6 途径相关的多种代谢物的水平在 3D 球体中显著改变。重要的是，我们表明，用降低维生素 B6 水平的小分子肼来进行药理学干预，导致 3D GBM 球体培养物的细胞死亡。因此，我们的研究表明，抑制维生素 B6 途径是开发 GBM 靶向治疗的一种新的治疗策略。
