Fenbendazole (FZ) is an anthelmintic drug used to treat intestinal parasites such as pinworms, giardiasis, hookworms and Taenia solium, as well as respiratory parasites like lungworms. However, this benzimidazole compound is now being repurposed by researchers to target cancer.
The anticancer activity of FZ stems from its polymerization inhibitory effects on tubulin, one of the major components of microtubules. Microtubules are a structural support system for cells, providing structure and shape to the cell. They are also involved in cell division, which is essential for maintaining the correct order of chromosomes during mitosis. During this phase, chromosomes are lined up at the metaphase stage and then evenly separated during anaphase through a mitotic spindle made of microtubules. Inhibition of tubulin polymerization prevents cell-cycle progression and leads to mitotic catastrophe.
In this study, fenbendazole was found to induce cell cycle arrest and apoptosis in 5-FU sensitive and resistant SNU-C5 and SNU-C5/5-FUR colorectal cancer cells. Wild-type p53 but not mutant p53 expression was increased in both cells following fenbendazole treatment. Nevertheless, apoptosis was not completely mediated by p53 activation. Instead, apoptosis was partially enhanced by ferroptosis via decreased expression of glutathione peroxidase 4 (GPX4) and Beclin-1.
GPX4 is a mitochondrial enzyme that is responsible for the production of reactive oxygen species (ROS), which are essential for ferroptosis. We found that fenbendazole significantly decreases ROS production in both SNU-C5 and SNU-C5/5-FUR cells. The inhibition of ROS by fenbendazole augmented apoptosis via p53-independent mechanisms, implying that oxidative stress is a significant mechanism for fenbendazole-induced cellular death. fenbendazole cancer