A new study suggests that fenbendazole, which is used to treat parasitic infections, may also have anti-cancer effects. The drug, which is known as mebendazole in humans, works by cutting off a cancer cell’s supply of nutrition by causing it to collapse. Researchers from the University of Virginia School of Medicine have discovered that fenbendazole also triggers a form of cell death called ferroptosis in colorectal cancer cells and patient-derived colon cancer organoids.
Despite its widespread use in animals, fenbendazole is not currently approved for human use. Nevertheless, research into its anti-cancer effects continues. In this latest work, the team found that fenbendazole reduces the proliferation of human colorectal cancer cells by triggering a form of cell death called ferroptosis, which is characterized by lipid peroxidation and inactivation of the lipid repair enzyme GPX4. This type of lipid peroxidation is induced by cellular stress and leads to activation of RIP1 and RIP3 kinases, resulting in phosphorylation of MLKL and caspase-8. Moreover, the researchers observed that fenbendazole triggered this form of cell death in 5-fluorouracil-resistant SNU-C5 cells.
To investigate the mechanism by which fenbendazole induces this form of cell death, they treated SNU-C5 and SNU-C5/5-FUR cells with different doses of fenbendazole. Then, the expression of several proteins associated with necroptosis was determined by immunoblotting. Proteins including RIP1, RIP3, phosphor-mixed lineage kinase domain-like protein (PLKL), MLKL, and caspase-8 were examined, and their signal intensity was analyzed by AzureSpot analysis software. GAPDH was used as a control.
The researchers also compared the results of their fenbendazole experiments with those of their previous findings on the anthelmintic drug mebendazole. They found that mebendazole also causes a type of cell death called ferroptosis, but this cell death process involves the uptake of iron from the cytoplasm rather than the degradation of the lipid bilayer. Furthermore, mebendazole induced less autophagy and did not require the p53 tumor suppressor in 5-fluorouracil-resistant cells.
Interestingly, the team also found that treatment with the anti-ferroptotic agents deferoxamine mesylate (DFOM) and ferrostatin-1 blocked the fenbendazole-induced cell viability. The results suggest that these anti-ferroptotic agents elicit synergistic apoptosis through increasing the DAMP levels in the cell, in addition to reducing the accumulation of free iron. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, grant number NRF-2019R1C1C1009996. Additional support came from the Virginia and D.K. Ludwig Fund for Cancer Research. The authors disclose no financial or other conflicts of interest. The article can be accessed at http://jbcr.org/cgi/content/full/jbcr2018/101/fenbendazole_and_cancer_cell_viability_via_ferroptosis.pdf. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License. Replication and distribution of this article are encouraged, provided that the original author and source are credited. The Journal of Biological Chemistry is published by the American Association for Cancer Research. fenbendazole stage 4 cancer