Fenbendazole (FZ) is a benzimidazole carbamate medication widely used as an antiparasitic drug with broad spectrum activity against parasitic infections in several animal species. It binds to -tubulin and disrupts its polymerization, blocking the formation of microtubules in the cell cytoskeleton and arresting the cell cycle. It also interferes with glucose uptake, reducing glycogen stores and ATP production in susceptible parasite cells. These anthelmintic properties, together with its lack of serious side effects in animals and humans, led to its repurposing as a potential cancer treatment.
Various cellular mechanisms have been associated with fenbendazole’s anticancer effect, including the inhibition of cell division by preventing microtubule formation, the stabilization of the p53 tumor suppressor, and the induction of cell death via autophagy, ferroptosis, or necroptosis. Moreover, it is known that fenbendazole can enhance the anticancer effects of chemotherapy drugs such as 5-FU and methotrexate in colorectal cancer cells.
In recent years, anecdotal accounts of fenbendazole curing cancer in humans have received widespread attention on social media. These accounts center on the story of a woman named Joe Tippens who was diagnosed with melanoma and found her CEA levels decreasing after taking oral fenbendazole for dogs based on advice from online sources. The patient reported a complete response to her cancer after three months of fenbendazole therapy, and her story became an internet sensation.
It has since been determined that fenbendazole, when combined with the anticancer agent dichloroacetate (DCA), can induce cancer remission in humans. Although these results have been deemed promising, more research is needed to fully understand the mechanism of fenbendazole for humans and how it can be used as an effective cancer treatment.
Recently, we analyzed the underlying mechanisms of fenbendazole’s potent anticancer effects in 5-FU-resistant human colorectal cancer cells. Fenbendazole induced preferential elimination of cancer cells in both wild-type and 5-FU resistant SNU-C5 cell lines through microtubule disruption, p53 stabilization, and interference with glucose metabolism. In addition, it induced apoptosis in these cells through the caspase-3-PARP pathway.
In our study, we identified a novel mechanism through which fenbendazole promotes preferential elimination of chemoresistant cancer cells by inducing apoptosis through the mitochondrial injury pathway. This mechanism involves the accumulation of reactive oxygen species in cells through the GPX4-dependent mitochondrial ROS-induced pathway, resulting in apoptosis and necroptosis. This study suggests that the fenbendazole-induced mitochondrial stress and ROS-mediated death pathway may represent a useful target to overcome 5-FU resistance in colorectal cancer. The fenbendazole-induced preferential elimination of chemoresistant cancers by combining microtubule disruption, p53 stability, and interference with glucose metabolism represents an exciting prospect for a new generation of drugs that combine repurposing as a veterinary anthelmintic with the anticancer activity of DCA.