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.

Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes

“…Niclosamide is also a potent inhibitor of SLC7A11 in breast cancer cell lines, consequently leading to the induction of ferroptosis [ 30 ]. The effect on intracellular pH is related to the function of niclosamide as a protonophore (i.e., a H + channel) [ 60 , 61 ], whereas the inhibitory effect of the drug on SLC38A5 and SLC7A11 is the result of its direct interaction with the two transporters. In the present study, we tested if niclosamide had similar effects in colon cancer cell lines.…”

Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes

“…Niclosamide is also a potent inhibitor of SLC7A11 in breast cancer cell lines, consequently leading to induction of ferroptosis [30]. The effect on intracellular pH is related to the function of niclosamide as a protonophore (i.e., a H + channel) [58,59] whereas the inhibitory effect of the drug on SLC38A5 and SLC7A11 is the result of its direct interaction with the two transporters. In the present study, we tested if niclosamide had similar effects in colon cancer cell lines.…”

The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides

“…The niclosamide salt with ethanolamine is distinctly more soluble in water (180–280 mg/L at 20 °C), and a piperazine salt of niclosamide has also been developed to improve aqueous solubility [ 22 , 23 ]. Of note, intramolecular H-bonding in salicylanilides can lead to two different conformations, the “open-ring” conformation (H-bond between OH and amide-NH) and the “closed-ring” conformation (H-bond between OH and amide-CO), depending on the ring substituents, which can have distinct effects on its biological activities [ 24 ].…”