The magic bullet: Niclosamide

Abstract

The term ‘magic bullet’ is a scientific concept proposed by the German Nobel laureate Paul Ehrlich in 1907, describing a medicine that could specifically and efficiently target a disease without harming the body. Oncologists have been looking for a magic bullet for cancer therapy ever since. However, the current therapies for cancers—including chemotherapy, radiation therapy, hormone therapy, and targeted therapy—pose either pan-cytotoxicity or only single-target efficacy, precluding their ability to function as a magic bullet. Intriguingly, niclosamide, an FDA-approved drug for treating tapeworm infections with an excellent safety profile, displays broad anti-cancer activity in a variety of contexts. In particular, niclosamide inhibits multiple oncogenic pathways such as Wnt/β-catenin, Ras, Stat3, Notch, E2F-Myc, NF-κB, and mTOR and activates tumor suppressor signaling pathways such as p53, PP2A, and AMPK. Moreover, niclosamide potentially improves immunotherapy by modulating pathways such as PD-1/PDL-1. We recently discovered that niclosamide ethanolamine (NEN) reprograms cellular metabolism through its uncoupler function, consequently remodeling the cellular epigenetic landscape to promote differentiation. Inspired by the promising results from the pre-clinical studies, several clinical trials are ongoing to assess the therapeutic effect of niclosamide in cancer patients. This current review summarizes the functions, mechanism of action, and potential applications of niclosamide in cancer therapy as a magic bullet.

A Mitochondrial Perspective on Noncommunicable Diseases

“…Reversing the Warburg effect might be an approach to restore cell differentiation in cancer. Haowen Jiang et al used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells [ 42 ]. The results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic therapy for reversing the Warburg effect and inducing differentiation in neuroblastoma.…”

A repurposed drug combination (VaN) inhibits free light chain secretion and triggers the terminal unfolded protein response (UPR) in multiple myeloma (MM)

“…Thus, alternative approaches targeting the proteostatic adaptations within MM cells will bring clinical bene t. Niclosamide (NIC) is a well-tolerated oral anti-helminthic drug used to treat parasitic infections worldwide(28). NIC has also been demonstrated to have potential anti-tumour activity against multiple cancers (reviewed in (29)(30)(31)(32)) and we previously demonstrated the anti-MM activity of NIC (33). Due to poor aqueous solubility, NIC has limited oral bioavailability and other groups have sought to modify its structure/delivery to improve solubility (31,34,35).…”

“…NIC has also been demonstrated to have potential anti-tumour activity against multiple cancers (reviewed in (29)(30)(31)(32)) and we previously demonstrated the anti-MM activity of NIC (33). Due to poor aqueous solubility, NIC has limited oral bioavailability and other groups have sought to modify its structure/delivery to improve solubility (31,34,35). We reasoned that an alternative, faster strategy is to seek adjuvant therapies that potentiate the anti-MM activity of standard NIC at currently achievable safe serum concentrations.…”

Targeting the epithelial–mesenchymal transition (EMT) pathway with combination of Wnt inhibitor and chalcone complexes in lung cancer cells

“…Niclosamide is an FDA‐approved anthelmintic drug for the treatment of parasitic infections (Figure 1A). 9 Beyond this anti‐helminthic activity, niclosamide also exhibits anticancer properties by inhibiting oncogenic pathways and activating tumor suppressor signaling pathways 10 . In addition, there are many studies in which niclosamide was combined with different agents 10 .…”

“… 9 Beyond this anti‐helminthic activity, niclosamide also exhibits anticancer properties by inhibiting oncogenic pathways and activating tumor suppressor signaling pathways 10 . In addition, there are many studies in which niclosamide was combined with different agents 10 . Akgun et al showed that niclozamide inhibited the Wnt/β‐Catenin pathway, which has a role in the EMT process, and that its combinations with histone deacetylase inhibitor valproic acid had a synergistic effect to kill lung cancer cells 11 …”