Salicylanilides and Their Anticancer Properties

Abstract

Salicylanilides are pharmacologically active compounds with a wide spectrum of biological effects. Halogenated salicylanilides, which have been used for decades in human and veterinary medicine as anthelmintics, have recently emerged as candidates for drug repurposing in oncology. The most prominent example of salicylanilide anthelmintic, that is intensively studied for its potential anticancer properties, is niclosamide. Nevertheless, recent studies have discovered extensive anticancer potential in a number of other salicylanilides. This potential of their anticancer action is mediated most likely by diverse mechanisms of action such as uncoupling of oxidative phosphorylation, inhibition of protein tyrosine kinase epidermal growth factor receptor, modulation of different signaling pathways as Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways or induction of B-Raf V600E inhibition. Here we provide a comprehensive overview of the current knowledge about the proposed mechanisms of action of anticancer activity of salicylanilides based on preclinical in vitro and in vivo studies, or structural requirements for such an activity.

Keywords: STAT3; TK EGFR; anticancer properties; drug repurposing; mitochondrial uncoupling; niclosamide; salicylanilides.

Figure 1

Structures of salicylanilides investigated for their potential anticancer properties.

Figure 2

Summary of the most frequently proposed mechanisms of niclosamide’s anticancer effect. RONS, reactive oxide and nitrogen species.

Figure 3

Conformational equilibrium in salicylanilide molecules. Two possible intramolecular hydrogen bond formations resulting in closed-ring or open-ring conformation [52].

Figure 4

Protonophore activity of niclosamide in the inner mitochondrial membrane. Scheme was created according to [60,61].

Figure 5

Structures of nitazoxanide and its metabolite tizoxanide.

Figure 6

Canonical NF-κB pathway as possible target of selective inhibitor of IKKβ IMD-0354. Upon wide variety of activating stimuli, trimeric complex that consists of catalytic subunits, IKKα and IKKβ, and a regulatory subunit NEMO could phosphorylate two serine residues of IκB bound to NF-κB dimers. NF-κB occurs mainly in the form of p50/p65 dimers. This phosphorylation leads to ubiquitination of IκB and its proteasome degradation. Thus NF-κB is translocated into the nucleus and modulates gene transcription. Scheme was created according to [133,137,138].

Figure 7

Synergistic activity of niclosamide with immune checkpoint inhibitors e.g., anti-PD-L1 or anti-PD-1 monoclonal antibodies. Niclosamide suppresses phosphorylation of STAT3 and thus downregulates the expression of PD-L1. Scheme was created according to [104,161].