Screening of Benzimidazole-Based Anthelmintics and Their Enantiomers as Repurposed Drug Candidates in Cancer Therapy

Abstract

Repurposing of approved non-antitumor drugs represents a promising and affordable strategy that may help to increase the repertoire of effective anticancer drugs. Benzimidazole-based anthelmintics are antiparasitic drugs commonly employed both in human and veterinary medicine. Benzimidazole compounds are being considered for drug repurposing due to antitumor activities displayed by some members of the family. In this study, we explored the effects of a large series of benzimidazole-based anthelmintics (and some enantiomerically pure forms of those containing a stereogenic center) on the viability of different tumor cell lines derived from paraganglioma, pancreatic and colorectal cancer. Flubendazole, parbendazole, oxibendazole, mebendazole, albendazole and fenbendazole showed the most consistent antiproliferative effects, displaying IC50 values in the low micromolar range, or even in the nanomolar range. In silico evaluation of their physicochemical, pharmacokinetics and medicinal chemistry properties also provided useful information related to the chemical structures and potential of these compounds. Furthermore, in view of the potential repurposing of these drugs in cancer therapy and considering that pharmaceutically active compounds may have different mechanisms of action, we performed an in silico target prediction to assess the polypharmacology of these benzimidazoles, which highlighted previously unknown cancer-relevant molecular targets.

Cationic Peptides and Their Cu(II) and Ni(II) Complexes: Coordination and Biological Characteristics

“…From this point of view, antimicrobial peptides (AMPs) seem to be attractive and promising tools in medical sciences. Additionally, many metallo-complexes characterized in recent years have been applied in the treatment of anti-inflammatory infections, cancer, and neurodegenerative diseases [ 1 , 2 , 3 , 4 ].…”

Exploring the Versatility of Benzimidazole Scaffolds as Medicinal Agents: A Brief Update

“…Drug repurposing of benzimidazole compounds is generally considered for the reason that, it has antitumor activities. Florio and coworkers screened anthelmintics which are derivatives of benzimidazole [37]. Certain drugs like albendazole (3), flubendazole (9), oxibendazole (10) etc.…”

Drug Repurposing, an Attractive Strategy in Pancreatic Cancer Treatment: Preclinical and Clinical Updates

“…Benzimidazole-based anthelmintics are a family of drugs widely employed both in human and in veterinary medicine for the treatment of intestinal parasites [104]. Interestingly, there is a growing number of studies reporting that several members of this family display both in vitro and in vivo antitumor effects in multiple tumor models, including PC [29,[105][106][107]. In particular, Florio et al showed that parbendazole (Figure 1), at dosages in the range of the therapeutic plasma concentrations, inhibits growth and abolishes clonogenicity of PC cells by fostering apoptosis, drastic cell cycle perturbation and DNA damage response [29].…”

“…Notably, the combined treatment of parbendazole with the PC standard chemotherapeutic drug gemcitabine synergistically affects PC cell viability, supporting the relevance of parbendazole in the perspective of clinical translation. Intriguingly, considering that pharmaceutically active compounds may modulate multiple molecular targets with a plethora of mechanisms of action, putative polypharmacological profiles of a wider series of benzimidazoles were explored by using an in silico target prediction approach [106]. Notably, for the two derivatives fenbendazole and mebendazole, the bioinformatic tool highlighted a few previously underexplored cancer-related targets having very high probability scores, namely MAP kinase p38 alpha, vascular endothelial growth factor receptor 2 (VEGFR2) and the tyrosine-protein kinase ABL [106].…”

“…Intriguingly, considering that pharmaceutically active compounds may modulate multiple molecular targets with a plethora of mechanisms of action, putative polypharmacological profiles of a wider series of benzimidazoles were explored by using an in silico target prediction approach [106]. Notably, for the two derivatives fenbendazole and mebendazole, the bioinformatic tool highlighted a few previously underexplored cancer-related targets having very high probability scores, namely MAP kinase p38 alpha, vascular endothelial growth factor receptor 2 (VEGFR2) and the tyrosine-protein kinase ABL [106]. Further in vitro and in vivo studies in PC and also in additional tumor models are needed to validate these predictions, in view of the potential repurposing of benzimidazole-based anthelmintics in oncology.…”