Jamali Fatemeh, Lan Katherine, Daniel Paul, Petrecca Kevin, Sabri Siham, Abdulkarim Bassam
Pathology Graduate and Postdoctoral Studies Program, Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada.
Cancer Research Program, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada.
Antioxidants (Basel). 2024 Oct 3;13(10):1201. doi: 10.3390/antiox13101201.
Glioblastoma (GBM) is an incurable primary brain cancer characterized by increased reactive oxygen species (ROS) production. The redox-sensitive tumor suppressor gene , wild-type (wt) for 70% of patients, regulates redox homeostasis. Glioblastoma stem cells (GSCs) increase thioredoxin (Trx) and glutathione (GSH) antioxidant systems as survival redox-adaptive mechanisms to maintain ROS below the cytotoxic threshold. Auranofin, an FDA-approved anti-rheumatoid drug, inhibits thioredoxin reductase 1 (TrxR1). L-buthionine sulfoximine (L-BSO) and the natural product piperlongumine (PPL) inhibit the GSH system. We evaluated the cytotoxic effects of Auranofin alone and in combination with L-BSO or PPL in GBM cell lines and GSCs with a known status. The Cancer Genome Atlas/GBM analysis revealed a significant positive correlation between wtp53 and TrxR1 expression in GBM. Auranofin induced ROS-dependent cytotoxicity within a micromolar range in GSCs. Auranofin decreased TrxR1 expression, AKT (Ser-473) phosphorylation, and increased p53, p21, and PARP-1 apoptotic cleavage in wtp53-GSCs, while mutant-p53 was decreased in a mutant-p53 GSC line. Additionally, p53-knockdown in a wtp53-GSC line decreased TrxR1 expression and significantly increased sensitivity to Auranofin, suggesting the role of wtp53 as a negative redox-sensitive mechanism in response to Auranofin in GSCs. The combination of Auranofin and L-BSO synergistically increased ROS, decreased IC50s, and induced long-term cytotoxicity irrespective of p53 in GBM cell lines and GSCs. Intriguingly, Auranofin increased the expression of glutathione S-transferase pi-1 (GSTP-1), a target of PPL. Combining Auranofin with PPL synergistically decreased IC50s to a nanomolar range in GSCs, supporting the potential to repurpose Auranofin and PPL in GBM.
胶质母细胞瘤（GBM）是一种无法治愈的原发性脑癌，其特征是活性氧（ROS）生成增加。氧化还原敏感的肿瘤抑制基因，70%的患者为野生型（wt），调节氧化还原稳态。胶质母细胞瘤干细胞（GSCs）增加硫氧还蛋白（Trx）和谷胱甘肽（GSH）抗氧化系统，作为生存氧化还原适应机制，以将ROS维持在细胞毒性阈值以下。金诺芬是一种经美国食品药品监督管理局（FDA）批准的抗类风湿药物，可抑制硫氧还蛋白还原酶1（TrxR1）。L-丁硫氨酸亚砜胺（L-BSO）和天然产物胡椒碱（PPL）可抑制GSH系统。我们评估了金诺芬单独使用以及与L-BSO或PPL联合使用对GBM细胞系和已知状态的GSCs的细胞毒性作用。癌症基因组图谱/GBM分析显示，GBM中wtp53与TrxR1表达之间存在显著正相关。金诺芬在微摩尔范围内诱导GSCs产生ROS依赖性细胞毒性。在wtp53-GSCs中，金诺芬降低TrxR1表达、AKT（Ser-473）磷酸化，并增加p53、p21和PARP-1的凋亡切割，而在突变型p53 GSC系中，突变型p53减少。此外，在wtp53-GSC系中敲低p53会降低TrxR1表达，并显著增加对金诺芬的敏感性，表明wtp53在GSCs中作为对金诺芬的负氧化还原敏感机制发挥作用。金诺芬与L-BSO联合使用可协同增加ROS、降低IC50，并在GBM细胞系和GSCs中诱导长期细胞毒性，而与p53无关。有趣的是，金诺芬增加了谷胱甘肽S-转移酶pi-1（GSTP-1）的表达，GSTP-1是PPL的一个靶点。在GSCs中，将金诺芬与PPL联合使用可协同将IC50降低至纳摩尔范围，支持在GBM中重新利用金诺芬和PPL的潜力。
