Benzimidazoles induce concurrent apoptosis and pyroptosis of human glioblastoma cells via arresting cell cycle

• 作者: Li-wen Ren Wan Li Xiang-jin Zheng Jin-yi Liu Yi-hui Yang Sha Li Sen Zhang Wei-qi Fu Bin Xiao Jin-hua Wang Guan-hua Du
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2022,（1）
• 所属期刊栏目: Cbemotherapy
• 页码范围: 194-208
• 页数: 15页
• 语种: 英文

摘要

Glioblastoma multiforme(GBM)is the most malignant and lethal primary brain tumor in adults accounting for about 50％of all gliomas.The only treatment available for GBM is the drug temozolomide,which unfortunately has frequent drug resistance issue.By analyzing the hub genes of GBM via weighted gene co-expression network analysis(WGCNA)of the cancer genome atlas(TCGA)dataset,and using the connectivity map(CMAP)platform for drug repurposing,we found that multiple azole compounds had potential anti-GBM activity.When their anti-GBM activity was examined,however,only three benzimidazole compounds,i.e.flubendazole,mebendazole and fenbendazole,potently and dose-dependently inhibited proliferation of U87 and U251 cells with IC50 values below 0.26 μM.Benzimidazoles(0.125-0.5 μM)dose-dependently suppressed DNA synthesis,cell migration and invasion,and regulated the expression of key epithelial-mesenchymal transition(EMT)markers in U87 and U251 cells.Benzimidazoles treatment also dose-dependently induced the GBM cell cycle arrest at the G2/M phase via the P53/P21/cyclin B1 pathway.Furthermore,the drugs triggered pyroptosis of GBM cells through the NF-KB/NLRP3/GSDMD pathway,and might also concurrently induced mitochondria-dependent apoptosis.In a nude mouse U87 cell xenograft model,administration of flubendazole(12.5,25,and 50 mg.kg-1·d-1,i.p,for 3 weeks)dose-dependently suppressed the tumor growth without obvious adverse effects.Taken together,our results demonstrated that benzimidazoles might be promising candidates for the treatment of GBM.