The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma and
Authors: Jingxuan Pan
Yizhi Liu
Jingfeng Zhou
Yanli Jin
Bei Jin
Journal: Theranostics (2017)
Discipline: CLINICAL MEDICINE
Keywords: cancer stem cells; invasion; migration; niclosamide; uveal melanoma.
Affiliations: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 S. Xianlie Road, Guangzhou, 510060, China.

Abstract:  Uveal melanoma (UM) is a lethal intraocular malignancy with an average survival of only 2~8 months in patients with hepatic metastasis. Currently, there is no effective therapy for metastatic UM. Here, we reported that niclosamide, an effective repellence of tapeworm that has been approved for use in patients for approximately 50 years, exhibited strong antitumor activity in UM cells in vitro and in vivo. We showed that niclosamide potently inhibited UM cell proliferation, induced apoptosis and reduced migration and invasion. p-Niclosamide, a water-soluble niclosamide, exerted potent in vivo antitumor activity in a UM xenograft mouse model. Mechanistically, niclosamide abrogated the activation of the NF-κB pathway induced by tumor necrosis factor α (TNFα) in UM cells, while niclosamide elevated the levels of intracellullar and mitochondrial reactive oxygen species (ROS) in UM cells. Quenching ROS by N-acetylcysteine (NAC) weakened the ability of niclosamide-mediated apoptosis. Matrix metalloproteinase 9 (MMP-9) knockdown by shRNA potentiated, while ectopic expression of MMP-9 rescued, the niclosamide-attenuated invasion, implying that MMP-9 is pivotal for invasion blockage by niclosamide in UM cells. Furthermore, our results showed that niclosamide eliminated cancer stem-like cells (CSCs) as reflected by a decrease in the Aldefluor+ percentage and serial re-plating melanosphere formation, and these phenotypes were associated with the suppressed Wnt/β-catenin pathway by niclosamide in UM. Niclosamide caused a dose- and time-dependent reduction of β-catenin and the key components [e.g., DVLs, phospho-GSK3β (S9), c-Myc and Cyclin D1] in the canonical Wnt/β-catenin pathway. Additionally, niclosamide treatment in UM cells reduced ATP and cAMP contents, and decreased PKA-dependent phosphorylation of β-catenin at S552 and S675 which determine the stability of β-catenin protein, suggesting that niclosamide may work as a mitochondrial un-coupler. Taken together, our results shed light on the mechanism of antitumor action of niclosamide and warrant clinical trial for treatment of UM patients. 

Retracted: No

PubPeer comments:
 Two actin bands in Fig. 2C look much more similar than you could expect. Could the authors please check? ![file] , 
 * Figure 2C similarities: These panels look somewhat similar but I am not sure if I would call them more similar than expected. Of course, the authors could take away any concern by positing the original blots. , 
 I would like to differ with the concerns posted by Platycheirus Stegnus in #1. Please Look at my detailed analysis below which shows that the beta-actin bands in the two panels are different. ![file] The differences in both the figures are indicated with boxes of the same colour. It can be clearly seen that the beta-actin bands in both figures show prominent differences. The shape of the bands and band size in the two pictures looks very different. Quite frankly, I feel the bands in both the figures are very different and there are no reasons to worry. , 
 #1 #2 #3 Dear Dr. Platycheirus Stegnus, Dr. Elisabeth M Bik and Dr. Pedicularis Glabrescens, I am the first author Jingfeng Zhou. Thank you very much for your interest in our work and pointing out the error in Figure 2C. After carefully checking the original data, I realized that when I was preparing Figure 2C with photoshop microsoftware, the Western blot of the u03b2-actin in 92.1 cells group was inadvertently duplicated with Mel270 cells group. The corrected bands and its source are shown below. The error did not affect the conclusions of the study. We deeply apologize for these unconscious mistakes during figure assembly. The authors will write to the Journal to request an erratum. Thanks. Jingfeng Zhou. ![file] ,