Fenbendazole in Stage 4 Colorectal Cancer
Fenbendazole, a commonly used antihelmintic drug, is an effective inhibitor of protein phosphatase and can inhibit the formation of phosphorylated mTOR complex 1, which regulates cell cycle progression. It also possesses antitumor activity by enhancing the cytotoxicity of doxorubicin and radiation in cancer cells. Additionally, benzimidazole has been shown to activate p53 and p21, suppress mutant p53 expression, and cause G2/M phase arrest, apoptosis, and autophagy. However, its underlying mechanism has not yet been fully determined.
In this study, we investigated the effects and underlying mechanisms of fenbendazole in 5-fluorouracil-resistant colorectal cancer cells (SNU-C5/5-FUR). We found that fenbendazole significantly sensitized the SNU-C5/5-FUR cells to 5-fluorouracil by causing apoptosis, cell cycle arrest, and autophagy. Moreover, we identified that the fenbendazole-induced autophagy is mediated by Beclin-1 and involves LC3-I and LC3-II. In addition, fenbendazole triggers the ferroptosis-augmented apoptosis by decreasing GPX4 expression. Furthermore, the fenbendazole-induced apoptosis and autophagy are independent of p53.
To assess the cellular response to fenbendazole, SNU-C5 and SNU-C5/5-FUR colorectal cancer cells were treated with different concentrations of fenbendazole in the presence or absence of deferoxamine mesylate (DFOM) for 3 days. Viability of the cells was measured by MTT assay. Cells were then harvested and subjected to immunoblot analysis with the indicated antibodies. Cells were also analyzed by flow cytometry for the detection of apoptosis and cell cycle. The results showed that fenbendazole induces apoptosis and G2/M phase cell cycle arrest in both wild-type and 5-fluorouracil-resistant colorectal tumor cells. In addition, fenbendazole enhanced the cytotoxicity of 5-fluorouracil in 5-fluorouracil-resistant SNU-C5/5-FUR colon cancer organoids and patient-derived colon tumors. These findings indicate that fenbendazole could be an effective agent in combination with chemotherapy to overcome the resistance of cancer cells to conventional treatments. fenbendazole stage 4 cancer