Mini-reviewMulti-targeted therapy of cancer by niclosamide: A new application for an old drug
Introduction
Niclosamide (trade name Niclocide), a teniacide in the anthelmintic family which is especially effective against cestodes, has been approved for use in humans for nearly 50 years (Fig. 1) [1], [2]. Niclosamide inhibits oxidative phosphorylation and stimulates adenosine triphosphatase activity in the mitochondria of cestodes (eg. tapeworm), killing the scolex and proximal segments of the tapeworm both in vitro and in vivo [2]. Niclosamide is well tolerated in humans. The treatment of Taenia saginata (beef tapeworm), Diphyllobothrium latum (fish tapeworm) and Dipylidium caninum (dog tapeworm) in adult is 2 g as a single oral dose. For the treatment of Hymenolepis nana (dwarf tapeworm), the same oral dose is used for 7 days [2].
Drug development, from the initial lead discovery to the final 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 potential anticancer agent by various high-throughput screening campaigns. This article reviews the current studies regarding various aspects of niclosamide as they relate to its potential new use in cancer therapy.
Section snippets
Niclosamide – a multiple pathway inhibitor for anti-cancer efficacy
Recently, several studies reported the inhibitory effects of niclosamide on multiple intracellular signaling pathways. The signaling molecules in these pathways are either over-expressed, constitutively active or mutated in many cancer cells, and thus render niclosamide as a potential anticancer agent. The effects of niclosamide on these pathways are described below.
Niclosamide targeting of mitochondria
Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. It has been proposed that targeting mitochondria is an efficient strategy for cancer chemotherapy [45]. Khanim et al. screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity, and identified niclosamide as a killer of multiple myeloma cell lines and primary multiple myeloma cells [30]. Interestingly, niclosamide anti-multiple myeloma
Anti-cancer activity of niclosamide: in vitro studies
Anti-cancer activity of niclosamide has been demonstrated in human breast cancer [10], [11], [18], [48], [49], prostate cancer [10], [29], colon cancer [9], [15], ovarian cancer [47], multiple myeloma [30], acute myelogenous leukemia [38], glioblastoma [12], head and neck cancer [21] and lung cancer cells [31]. As summarized in the earlier sections, niclosamide is able to block the multiple signaling pathways that govern cancer initiation and progression, thus it is not surprising that
Anti-cancer activity of niclosamide: in vivo studies
The efficacy of niclosamide has been shown against tumor growth and metastases in several xenograft models. Jin et al. demonstrated for the first time that niclosamide has in vivo anti-cancer activities [38]. As niclosamide has limited solubility in water, Jin et al. synthesized a niclosamide analog – phosphate of niclosamide (p-niclosamide), and found p-niclosamide showed significant inhibition of xenograft tumor growth of acute myeloid leukemia HL-60 cells by suppressing the NF-κB pathway [38]
Niclosamide as a drug for targeting CSCs
Current cancer treatments such as chemotherapy, targeted therapy and radiotherapy are successful at destroying bulk cancer cells, but fail to eliminate cancer stem cells (CSCs). CSCs are characterized by tumorigenic properties and the ability to self-renew, form differentiated progeny, and develop resistance to therapy. The inability to eradicate CSCs is thought to be the reason for cancer relapse and chemo-resistance, the major obstacles in current cancer therapy [57], [58], [59]. The
Challenges to using niclosamide as an anti-cancer agent in humans
The oral dose of niclosamide for adult in cestocidal treatment is 2 g as a single dose, leading to maximal serum concentrations of 0.25–6.0 μg/ml (corresponding to 0.76–18.35 μM) [1], which is well within the anti-cancer active concentration range. The reason for this wide range of serum concentrations is considered to be due to intra-individual difference in absorption rate [1]. Niclosamide has poor water solubility, and the oral bioavailability of niclosamide was only 10% in male Sprague-Dawley
Future directions
While considerable high-throughput screening campaigns have identified niclosamide is a potent inhibitor of a number of biological signaling pathways that mediate niclosamide’s anti-cancer effects in vitro and in vivo, direct targets of niclosamide still remain unclear. Niclosamide was tested in vitro against a panel of 95 protein kinases, and it did not significantly inhibit any of these kinases at concentrations (1 or 10 μM) efficiently inhibiting the Wnt/β-catenin, mTORC1, STAT3, NF-κB and
Conflict of Interest
The authors declare that they have no conflict of interest.
Acknowledgments
We thank Meredith S. Plaxco and Tommie A. Gamble for running the 60 human tumor cell line anticancer drug screen. This work was completed with the support of Grants from the National Institute of Health (R01CA124531 and R21CA182056 to Y. Li).
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