Repurposing of Benzimidazole Anthelmintic Drugs as Cancer Therapeutics

Abstract

Benzimidazoles have shown significant promise for repurposing as a cancer therapy. The aims of this review are to investigate the possibilities and limitations of the anti-cancer effects of benzimidazole anthelmintics and to suggest ways to overcome these limitations. This review included studies on the anti-cancer effects of 11 benzimidazoles. Largely divided into three parts, i.e., preclinical anti-cancer effects, clinical anti-cancer effects, and pharmacokinetic properties, we examine the characteristics of each benzimidazole and attempt to elucidate its key properties. Although many studies have demonstrated the anti-cancer effects of benzimidazoles, there is limited evidence regarding their effects in clinical settings. This might be because the clinical trials conducted using benzimidazoles failed to restrict their participants with specific criteria including cancer entities, cancer stages, and genetic characteristics of the participants. In addition, these drugs have limitations including low bioavailability, which results in insufficient plasma concentration levels. Additional studies on whole anti-cancer pathways and development strategies, including formulations, could result significant enhancements of the anti-cancer effects of benzimidazoles in clinical situations.

Keywords: anthelmintic drugs; benzimidazole; cancer therapy; repurposing.

Figure 1

Schematic diagram of anti-cancer mechanisms of benzimidazoles. (A) Effects of benzimidazoles on cancer cell death, (B) Anti-angiogenic and anti-metastatic effects of benzimidazoles, (C) Inhibitory effects of benzimidazoles on cancer stemness. Abbreviations: Mdm2: mouse double minute 2 homolog; MdmX: mouse double minute 4; RAF: rapidly accelerated fibrosarcoma; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinases; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; LC3: microtubule-associated protein 1 light chain 3; mTOR: mammalian target of rapamycin; PARP: poly(ADP-ribose) polymerase; Bax: B-cell lymphoma 2 (Bcl-2)-associated X protein; Bcl-2: B-cell lymphoma 2; Bcl-xL: B-cell lymphoma extra-large; VEGF: vascular endothelial growth factor; HIF: hypoxia-inducible factor; STAT3: signal transducer and activator of transcription 3; BCSC: breast cancer stem cell.