Fenben Induces Cell Death in Colorectal Cancer Cells

Fenben is a benzimidazole anthelmintic agent that was recently repurposed to overcome drug resistance in 5-fluorouracil-resistant colorectal cancer cells. In the present study, we investigated various cell death pathways induced by fenben in both wild-type and 5-FU resistant SNU-C5/5-FUR CRC cells. We found that fenbendazole induces G2/M arrest via p53-p21 pathways in both 5-FU sensitive and resistant cells. In case of apoptosis, it promotes p53-dependent apoptosis but also enhances ferroptosis-augmented apoptosis in both cell types. Furthermore, fenbendazole significantly increases the susceptibility of 5-FU-resistant CRC cells to ionizing radiation.

We first investigated the radiation dose-response curves of aerobic and hypoxic EMT6 cells treated with graded amounts of fenbendazole for 2 or 24 h. The results showed that the treatment significantly decreased the number of colonies produced in a colony formation assay. These data were complemented by flow cytometric analysis of cultures that were either treated for the same amount of time under normal air or severe hypoxia.

Severe hypoxia augmented the sensitivity of cells to fenbendazole (Fig. 1A). In contrast, normal air did not affect the sensitivity of cultures to this compound. 2-h incubation with fenbendazole resulted in a steep decrease of the viability of both aerobic and hypoxic EMT6 cells, whereas the viability of nontreated cultures remained nearly unchanged. This effect was accompanied by significant reductions of the clonogenicity of EMT6 cells, indicated by yield-corrected surviving fractions, which are a measure of the fraction of surviving tumor cells in the cultures at the end of a growth assay.