Multi-targeted therapy of cancer
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).
