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

Li-wen Ren1,2, Wan Li1,2, Xiang-jin Zheng1,2, Jin-yi Liu1,2, Yi-hui Yang1,2, Sha Li1,2, Sen Zhang1,2, Wei-qi Fu1,2, Bin Xiao3, Jin-hua Wang1,2, Guan-hua Du1,2
1 The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
2 Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
3 Laboratory of Clinical Pharmacy, Ordos School of Clinical Medicine, Inner Mongolia Medical University, Ordos 017099, China
Correspondence to: Jin-hua Wang:, Guan-hua Du:,
DOI: 10.1038/s41401-021-00752-y
Received: 9 April 2021
Accepted: 27 July 2021
Advance online: 25 August 2021


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-κB/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.
Keywords: glioblastoma; benzimidazoles; cell cycle arrest; apoptosis; pyroptosis; drug repurposing

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