Fenbendazole for Humans

Fenbendazole is a benzimidazole antihelmintic agent that has been recently repurposed to overcome resistance to 5-fluorouracil in cancer patients [1]. We previously reported that fenbendazole, unlike albendazole, significantly increases the sensitivity of colorectal carcinoma cells to 5-FU. However, the underlying mechanisms of fenbendazole-induced antitumor effects and 5-FU resistance remain unclear. To investigate these issues, cell viability and apoptosis were assayed in wild type and 5-FU-resistant SNU-C5 colorectal cancer cells treated with fenbendazole, and autophagy, ferroptosis, and necroptosis were investigated using Western blot analysis. The results showed that fenbendazole remarkably inhibited cell proliferation and induced apoptosis in both wild type and 5-FU-resistant cells, suggesting its role as an antitumor drug. Moreover, fenbendazole induced apoptosis through p53-p21 pathways in both wild type and 5-FU-resistant SNU-C5 cells, as well as mitochondrial injury marker, cytochrome-C expression, and autophagy via Beclin-1 induction.

Additionally, fenbendazole reduced the expression of the cysteine uptake protein SLC7A11 and GPX4 in both wild type and 5-FU-resistant cancer cells, resulting in diminished autophagy and ferroptosis. These findings demonstrate that fenbendazole induces apoptosis in 5-FU-resistant colorectal cancer cells through p53-dependent and -independent pathways, as well as lipid peroxidation-induced ferroptosis.

Our data also indicate that fenbendazole triggers necroptosis in 5-FU-resistant colorectal carcinoma cells by enhancing mitochondrial stress and triggering caspase-3 activation, which suggests the possibility that the synergistic effect of fenbendazole with chemotherapeutic agents may be beneficial in treating cancer patients with multidrug resistance. This study was supported by the National Research Foundation of Korea (NRF) grant 2014M3-A21001504. The authors thank Dr. Yong-Kyun Shin and Dr. Soo-Hyang Lee for their technical assistance.fenbendazole for humans