Fenbendazole and Stage 4 Colorectal Cancer

Kyung-Sun Kang, Da-Hyun Kim
Febendazole (FZ) is a widely used antihelminth agent that also exhibits antitumor activity as an oral chemotherapy. In combination with radiation or docetaxel, FZ has additive cytotoxicity against EMT6 mouse mammary tumor cells in cell culture and as solid tumors in mice. To investigate the mechanism of antitumor effects of fenbendazole in conjunction with these antineoplastic agents, we studied FZ-induced alterations in the cell cycle and in necroptosis using a model of severe hypoxia. We found that FZ inhibits cellular proliferation by binding beta-tubulin and disrupting microtubules, a phenomenon that is potently enhanced in the presence of severe hypoxia. Moreover, we found that FZ induces apoptosis via the p53-p21 pathways in 5-FU sensitive and resistant CRC cells, but not through autophagy or ferroptosis. The primary apoptotic pathway of fenbendazole is through the mitochondrial signaling pathway and it involves the activation of caspase-3-PARP. In contrast, fenbendazole does not significantly increase the expression of necroptosis-related proteins such as phosphor-mixed lineage kinase domain-like protein 1 (pMLKL) and caspase-8 in either sensitivity or resistance to 5-FU. Nevertheless, these findings suggest that the mitochondrial cell death pathways of fenbendazole and the underlying molecular mechanisms may be distinct from each other. These results support the hypothesis that fenbendazole could be useful as an adjunct to the current therapy of metastatic colorectal cancer in patients with a high risk of developing resistance to 5-FU or other chemotherapeutic agents. fenbendazole stage 4 cancer