Abstract

The rapid development of new anticancer

drugs that are safe and effective is a common goal shared by basic scientists,

clinicians and patients. The current review discusses one such agent, namely

niclosamide, which has been used in the clinic for the treatment of intestinal

parasite infections. Recent studies repeat-edly identified niclosamide as a

potential anticancer agent by various high-throughput screening cam-paigns.

Niclosamide not only inhibits the Wnt/b-catenin, mTORC1, STAT3, NF-jB and Notch

signaling pathways, but also targets mitochondria in cancer cells to induce

cell cycle arrest, growth inhibition and apoptosis. A number of studies have

established the anticancer activities of niclosamide in both in vitro and in

vivo models. Moreover, the inhibitory effects of niclosamide on cancer stem

cells provide further evidence for its consideration as a promising drug for

cancer therapy. This article reviews various aspects of niclosamide as they

relate to its efficacy against cancer and associatedmolecular mechanisms.

Introduction

Niclosamide (trade name Niclocide), ateniacide in the anthel-mintic family which is especially effective againstcestodes, has beenapprovedforuseinhumansfornearly50 years(Fig.1)[1,2]. Niclosamideinhibits oxidative phosphorylation and stimu-lates adenosine triphosphataseactivity in the mitochondria of ces-todes (eg. tapeworm), killing the scolexand proximal segments of the tapeworm both in vitro and in vivo [2].Niclosamide is well tolerated in humans. The treatment of Taenia saginata (beeftape-worm),Diphyllobothriumlatum(fishtapeworm)andDipylidiumcaninum (dog tapeworm) in adult is 2 g as a single oral dose. For the treatmentof Hymenolepis nana (dwarf tapeworm), the same oral dose is used for 7 days[2].

Drug development, from the initial lead

discovery to thefinal medication, is an expensive, lengthy

and incremental process [3]. Finding new uses for old or failed drugs is much

faster and more economical than inventing a new drug from scratch, as existing drugs

have known pharmacokinetics and safety profiles and have often

been approved for human use, therefore any newly identified use(s) can be rapidly evaluated in clinical trials [4]. In the

last 5 years niclosamide has been identified as a potentialanticancer agent by various high-throughput screening campaigns. This arti-clereviews the current studies regarding various aspects of niclo-samide as theyrelate to its potential new use in cancer therapy.

Niclosamide – a multiple pathway inhibitorfor anti-cancer efficacy

Recently, several studies reported theinhibitory effects of niclo-samide on multiple intracellular signalingpathways. The signaling molecules in these pathways are either over-expressed,constitu-tively activeor mutated inmany cancercells, andthus render niclosamide as a potentialanticancer agent. The effects of niclosa-mide on these pathways are describedbelow.

The Wnt/b-catenin pathway

The Wnt/b-catenin signaling pathway

regulates cancer progres-sion, including tumor initiation, tumor growth, cell

senescence, cell death, differentiation and metastasis [5–7]. In the absence of

Wnt, b-catenin is sequestered in a complex that consists of the adenomatous

polyposis coli (APC) tumor suppressor, axin, glycogen synthase kinase-3b

(GSK3b), and casein kinase 1 (CK1). This complex formation induces the

phosphorylation of b-catenin by CK1 and GSK3b, which results in the

ubiquitination and subsequent degradation of b-catenin by the 26S proteasome.

Conversely, when Wnt proteins form a ternary complex with the cell surface

recep-tors, low-density lipoprotein receptor-related protein5/6 (LRP5/6) and

Frizzled (Fzd), signaling from Wnt receptors proceeds through the proteins

dishevelled (Dvl) and axin, leading to the inhibition of GSK3b and the

stabilization of cytosolic b-catenin. The b-catenin then translocates into the

nucleus where it interacts with T-cell factor/lymphoid enhancing factor (TCF/LEF)

to induce the expres-sion of specific target genes [5–7] (Fig. 2A).