Drug repurposing and relabeling for cancer therapy: Emerging benzimidazole antihelminthics with potent anticancer effects

Origin of drug and radio-refractory clones, cancer stem-like cells, and rapid angiogenesis and metastasis are among the primary concerns that limit the efficacy of anticancer treatments, emphasizing the urgency of developing new therapeutics. Factors like high attrition rates, huge investments, patients' heterogeneity, and diverse molecular subtypes have challenged the rapid development of anticancer drugs. Treatment with repurposing pleiotropic benzimidazole antihelminthics, like mebendazole, albendazole, and flubendazole has recently opened a new window, owing to their easy access, low cost as a generic drug, and long track record of safe use in the human population. This review highlights the outcomes of preclinical and clinical studies of these drugs as a potent anticancer agent(s) conducted in the last two decades. Substantial preclinical studies, as well as limited clinical trials, suggest noteworthy anticancer potency of these pleiotropic benzimidazoles, particularly as potent microtubule disrupting, anti-angiogenic, and anti-metastatic agents, inhibitors of the immune checkpoint, hypoxia-inducible factor, epithelial-mesenchymal transition, cancer stemness, and multidrug resistance protein 1, and inducers of apoptosis and M1 polarization. These anticancer effects are attributed to multiple action points, including intrinsic apoptosis, canonical Wnt/β-catenin, JAK/STAT-3, JNK, MEK/ERK, and hedgehog signaling pathways. The effective anticancer properties of mebendazole, albendazole, and flubendazole either alone or synergistically with frontline drugs, warrant their validation through controlled clinical trials to use them as promising avenues to anticancer therapy.