J Cancer 2020; 11(12):3454-3466. doi:10.7150/jca.41418

Research Paper

Niclosamide inhibits ovarian carcinoma growth by interrupting cellular bioenergetics

Fugen Shangguan1,2*, Yan Liu3*, Li Ma3, Guiwu Qu4, Qing Lv4, Jing An5, Shude Yang6, Bin Lu1✉, Qizhi Cao3,4✉

1. Protein Quality Control and Diseases Laboratory, Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
2. Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
3. Department of Immunology, School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
4. Anti-aging Research Institution, Binzhou Medical University, Yantai, Shandong 264003, P.R.China
5. School of Medicine, University of California - San Diego, La Jolla, CA 92037, USA
6. School of Agriculture, Ludong University, Yantai, Shandong 264025, P.R.China
*These authors contributed equally to this work.

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Citation:
Shangguan F, Liu Y, Ma L, Qu G, Lv Q, An J, Yang S, Lu B, Cao Q. Niclosamide inhibits ovarian carcinoma growth by interrupting cellular bioenergetics. J Cancer 2020; 11(12):3454-3466. doi:10.7150/jca.41418. Available from http://www.jcancer.org/v11p3454.htm

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Abstract

Background: Ovarian carcinoma is a common malignant tumor of the female reproductive organs with an incidence rate second only to cervical and endometrial cancers. In the past 10 years, anticancer therapy has focused on Niclosamide, an anthelmintic teniacide that is commonly used against tapeworms and has been approved for use in humans for nearly 50 years. Importantly, Niclosamide has been confirmed to target the Wnt/β-catenin, mTOR, STAT3, NF-κB, and Notch pathways has been widely investigated in multiple cancer types. However, the potential benefits of Niclosamide therapy for treatment of ovarian carcinoma have not been established.

Methods: CCK-8 colony formation assays were performed to evaluate cell viability and tumor growth. Cell apoptosis was measured by flow cytometry. A Seahorse XF96 analyzer was used to measure cellular bioenergetics. Mito-tracker stained mitochondria were visualized by confocal microscopy. Western blotting was used to detect expressed proteins. A nude mouse transplanted-tumor model was used to evaluate the antitumor activity of Niclosamide in ovarian carcinoma.

Result: Niclosamide treatment significantly suppressed ovarian carcinoma growth and induced cell apoptosis by inactivating MEK1/2-ERK1/2 mediated signal transduction. Overall, mitochondrial respiration and aerobic glycolysis were both decreased by Niclosamide treatment. Niclosamide dramatically enhanced ROS-activated and JNK-mediated apoptosis in cells subjected to glucose deprivation. Niclosamide also showed in vivo antitumor activity in the nude mouse transplanted-tumor model.

Conclusion: Collectively, these data highlight a novel anti-tumor mechanism of Niclosamide that involves an interruption of cell metabolism. The finding also indicates a potential for the application of Niclosamide in ovarian carcinoma therapy.

Keywords: Niclosamide, ovarian carcinoma, cellular bioenergetics, MEK1/2-ERK1/2 signal