Fenbendazole in Stage 4 Colorectal Cancer

Fenbendazole (FZ) is a broad-spectrum benzimidazole anthelmintic drug approved for use in numerous animal species. Repurposing veterinary drugs with promising results in human disease can significantly reduce the time and cost of developing new drugs7. FZ displays moderate microtubule depolymerizing activity and has antitumor effects in colorectal cancer cells, including promoting ferroptosis.

To determine the mechanism by which fenbendazole inhibits the growth of 5-fluorouracil resistant tumor cells, the viability of wild-type and 5-fluorouracil-resistant SNU-C5 and SNU-C5/5-FUR colorectal cancer cells was assayed after treatment with varying concentrations of fenbendazole. Western blot and flow cytometry were performed to evaluate various cell death pathways. We found that fenbendazole significantly inhibited the proliferation of both cancer cells, with greater potency in SNU-C5/5-FUR cells than in wild-type cells. Furthermore, fenbendazole induced apoptosis, cell cycle arrest and mitochondrial injury in both cells. Apoptosis was mediated by p53 and p21 pathways, caspase-3 and poly (ADP-ribose) polymerase (PARP) activation, and cytochrome-C expression. Cell cycle arrest was mediated by p53 and senescence, and autophagy was induced by LC3-light chain-3 and Beclin-1 expression.

We also showed that fenbendazole significantly reduced glucose uptake in both cancer cells, a phenomenon that is largely caused by differential energy metabolism between normal and cancer cells. Cancer cells consume several folds more glucose than normal cells to generate ATP, which can be partially countered by depriving them of glucose supply. Interestingly, a number of benzimidazoles have been shown to interfere with energy metabolism by binding to tubulin and disrupting the microtubule equilibrium in lower organisms, and this might account for their antiparasitic efficacy. fenbendazole stage 4 cancer






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