Fenbendazole (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl) carbamate) is a broad-spectrum benzimidazole anthelmintic approved for use in many animal species. Repurposing veterinary drugs that show promising results in cancer treatment may reduce time and costs required for the development of novel anticancer agents.
In this study, we evaluated the effects of fenbendazole in human colorectal cancer cells. We found that fenbendazole inhibits glucose uptake by blocking the expression of GLUT transporters and hexokinase II, which is required for glucose production, and triggers ferroptosis and apoptosis in cancer cells. Moreover, fenbendazole significantly increases DAMP levels, which triggers synergistic apoptosis in cancer cells.
The toxicity of fenbendazole is mediated by p53-dependent and -independent pathways, and it activates p21 in 5-fluorouracil-sensitive and -resistant SNU-C5 cells. It also induces cell cycle arrest in p53 mutant and wild-type cells, as well as apoptosis through a mitochondrial-mediated pathway in p53-mutant SNU-C5 cells. It also blocks the growth of human xenografts in mice.
In addition, fenbendazole was found to increase radiation sensitivity in hypoxic and aerobic EMT6 cancer cells by increasing their necroptosis response to radiotherapy. However, the radiation dose-response curves for aerobic and hypoxic cells were not affected by fenbendazole pretreatment. The fenbendazole-induced increase in necroptosis was confirmed by immunoblotting using antibodies against phosphor-receptor-interacting protein kinase (pRIP), RIP3, phosphor-mixed lineage kinase domain-like protein (pMLKL), caspase-8, and GAPDH as a loading control. This result suggests that fenbendazole may be an effective radiosensitizer for CRC by activating the p53-dependent and -independent necroptosis pathways. fenbendazole cancer