The benzimidazole compound fenbendazole (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl) carbamate) is an established broad spectrum antiparasitic agent with extensive safety data in different species. It exerts its anthelmintic activities by binding to b-tubulin microtubule subunits and disrupting tubulin polymerization. It has also been reported to exhibit antitumor activities in various animal models.
The authors reported that an 80-year-old woman developed severe liver injury despite receiving standard pembrolizumab monotherapy for advanced nonsmall cell lung cancer (NSCLC). She subsequently disclosed to us that she had been self-administering oral fenbendazole, a dog deworming drug, since July 2019, solely based on social media reports suggesting its effectiveness against cancer. She stopped taking fenbendazole, and her liver injury resolved spontaneously.
In vitro, fenbendazole displayed time-dependent antiproliferative effects in 5-FU-sensitive SNU-C5 and SNU-C5/5-FUR CRC cells. These effects were partially mediated by p53-induced apoptosis and autophagy, but largely attributed to triggering ferroptosis and necroptosis. Necroptosis is triggered by mitochondrial injury and apoptotic signals involving phosphatidylinositol 3-phosphate (PI3P)/caspase-3-poly (ADP-ribose) polymerase (PARP) pathways, which are negatively regulated by the expression of MLKL.
MLKL expression was downregulated by fenbendazole in both CRC cell lines, leading to inactivation of the free iron uptake protein SLC7A11 and lipid repair enzyme GPX4. These events resulted in increased lipid peroxidation and ferroptosis. Treatment with the iron chelator DFOM or ferrostatin-1, which inhibits SLC7A11-dependent ferroptosis, did not block fenbendazole-induced cytotoxicity. This suggests that ferroptosis is the primary death pathway in fenbendazole-induced anti-cancer effects. In addition, fenbendazole induced synergistic apoptosis in cancer cells by increasing the pro-apoptotic factor dNADPH:cyclic AMP ratio and decreasing the tumor suppressor p53. fenbendazole for humans cancer