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.

Keywords: anti-tumor effect; epigenetics; magic bullet; metabolism; mitochondrial uncoupler; niclosamide; oncogenic pathways; tumor suppressors.

Figure 1

The structure of niclosamide (A) The structure and formulation of niclosamide. (B) The structure of salicylamides, which are weakly acidic phenolic compounds consisting of two basic chemical structures: a salicylic acid ring and an anilide ring.

Figure 2

Mitochondrial uncoupling reprograms metabolism and epigenetic landscape (A) Mitochondrial uncouplers dissipate the proton gradients which are essential to ATP synthesis, resulting in reduction of ATP/ADP ratio. When proton gradient reduce, the electron transfer chain, particularly complex I, are activated, leading to increased intracellular redox NAD⁺/NADH ratio. Given the NAD⁺/NADH ratio is the major driving force for TCA cycle, the oxidative TCA cycle and glutaminolysis are accelerated. Because the chemical equilibrium of many metabolites pair such as α-KG/2-HG and pyruvate and lactate (not show in the figure) are dictating by NAD⁺/NADH ratio. Thus, increased NAD⁺/NADH mediated by mitochondrial uncoupler shift the equilibrium from 2-HG to α-KG, resulting in increased α-KG/2-HG ratio. In the other hand, opposite to the oxidative TCA cycle, the reductive TCA cycle particular reductive carboxylation is inhibited by mitochondrial uncoupler. (B) The increased α-KG/2-HG ratio activates the α-KG-dependent dioxygenases such as TET and PHD, leading to DNA demethylation and HIFs protein degradation. These epigenetic rewiring activate the expression of differentiation makers and repress the stemness genes, consequently, cell differentiation. Created with >BioRender.com.

Figure 3

Niclosamide activates tumor suppressors and inhibits oncogenic pathways. Niclosamide has anti-tumor effect through inhibiting multiple oncogenic pathways such as Wnt/β-catenin, Ras, Stat3, Notch, E2F-Myc, NF-κB and mTOR, and activating tumor suppressor signaling such as p53, PP2A and AMPK. Created with BioRender.com.

Figure 4

Niclosamide inhibits Wnt pathway through multiple mechanism. The Wnt pathway inhibition by niclosamide depends on multiple ways of action: (1) Niclosamide suppresses LRP6 expression. (2) Niclosamide promotes the degradation of Frizzled 1 and Dishevelled-2 through autophagy. (3) Niclosamide binds GSK3 directly, resulting in disruption of the Axin-GSK3 complex and attenuation of canonical Wnt activity. Created with BioRender.com.