Anthelminthic niclosamide inhibits tumor growth and invasion in cisplatin‑resistant human epidermal growth factor receptor 2‑positive breast cancer

Liu,Junjun; Ding,Hanzhi; Quan,Hong; Han,Jing

doi:10.3892/ol.2021.12927

Anthelminthic niclosamide inhibits tumor growth and invasion in cisplatin‑resistant human epidermal growth factor receptor 2‑positive breast cancer

Authors:
- Junjun Liu
- Hanzhi Ding
- Hong Quan
- Jing Han
View Affiliations

Affiliations: Department of Breast Surgery, Shanghai East Hospital, Tongji University, Shanghai 200120, P.R. China
Published online on: July 14, 2021 https://doi.org/10.3892/ol.2021.12927
Article Number: 666
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Chemotherapy‑resistant breast cancer displays aggressive clinical behavior, is poorly differentiated and is associated with the occurrence of epithelial‑mesenchymal transition and the presence of cancer stem cells. The anthelmintic drug niclosamide has been shown to have numerous clinical applications in the treatment of malignant tumors, in addition to its traditional use in tapeworm disease. Our previous study demonstrated that niclosamide had an antiproliferative effect and could inhibit the stem‑like phenotype of the breast cancer cells, suggesting that it might have the potential to be used in the treatment of triple‑negative breast cancer. However, the specific function and underlying mechanism of action of niclosamide in chemoresistant human epidermal growth factor receptor 2 (HER2)‑positive breast cancer remain unknown. The present study aimed to determine whether niclosamide can inhibit cell proliferation, invasion and epithelial‑to‑mesenchymal transition, as well as the stem‑like phenotype in cisplatin‑resistant HER2‑positive breast cancer. Alamar Blue and Annexin V/7‑AAD staining, mammosphere formation and Transwell assays were performed to assess the viability, apoptosis, stem‑like phenotype and invasion ability of breast cancer cell lines, respectively. Signaling molecule expression was detected via western blotting and a xenograft model was used to verify the inhibitory effect of niclosamide in vivo. The results from the present study demonstrated that niclosamide inhibited the resistance of HER2‑positive breast cancer to cisplatin both in vitro and in vivo. Furthermore, niclosamide combined with cisplatin could inhibit breast cancer cell invasion, epithelial‑mesenchymal transition and cell stemness. The inhibitory effect of niclosamide was mediated by apoptosis induction and Bcl‑2 downregulation. Taken together, the results of the present study suggested that niclosamide combined with cisplatin may be considered as a novel treatment for chemoresistant HER2‑positive breast cancer.

View Figures

View References

1	Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, Nielsen TO and Gelmon K: Metastatic behavior of breast cancer subtypes. J Clin Oncol. 28:3271–3277. 2010. View Article : Google Scholar : PubMed/NCBI
2	Camejo N, Castillo C, Alonso R, Correa F, Rivero E, Mezquita C, Rosich A, Dellacasa F, Silveira L and Delgado L: Effectiveness of Trastuzumab for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in a Real-Life Setting: One Decade of Experience Under National Treatment Coverage Regulations. JCO Glob Oncol. 6:217–223. 2020. View Article : Google Scholar : PubMed/NCBI
3	Diaby V, Tawk R, Sanogo V, Xiao H and Montero AJ: A review of systematic reviews of the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy for breast cancer. Breast Cancer Res Treat. 151:27–40. 2015. View Article : Google Scholar : PubMed/NCBI
4	Geng SQ, Alexandrou AT and Li JJ: Breast cancer stem cells: Multiple capacities in tumor metastasis. Cancer Lett. 349:1–7. 2014. View Article : Google Scholar : PubMed/NCBI
5	Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar : PubMed/NCBI
6	Dean M, Fojo T and Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer. 5:275–284. 2005. View Article : Google Scholar : PubMed/NCBI
7	Samanta D, Gilkes DM, Chaturvedi P, Xiang L and Semenza GL: Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proc Natl Acad Sci USA. 111:E5429–E5438. 2014. View Article : Google Scholar : PubMed/NCBI
8	Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, et al: Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 100:672–679. 2008. View Article : Google Scholar : PubMed/NCBI
9	Gao J, Liu J, Xie F, Lu Y, Yin C and Shen X: Co-Delivery of Docetaxel and Salinomycin to Target Both Breast Cancer Cells and Stem Cells by PLGA/TPGS Nanoparticles. Int J Nanomedicine. 14:9199–9216. 2019. View Article : Google Scholar : PubMed/NCBI
10	Andrews P, Thyssen J and Lorke D: The biology and toxicology of molluscicides, Bayluscide. Pharmacol Ther. 19:245–295. 1982. View Article : Google Scholar : PubMed/NCBI
11	Chen B, Wei W, Ma L, Yang B, Gill RM, Chua MS, Butte AJ and So S: Computational Discovery of Niclosamide Ethanolamine, a Repurposed Drug Candidate That Reduces Growth of Hepatocellular Carcinoma Cells In Vitro and in Mice by Inhibiting Cell Division Cycle 37 Signaling. Gastroenterology. 152:2022–2036. 2017. View Article : Google Scholar : PubMed/NCBI
12	Al-Hadiya BM: Niclosamide: Comprehensive profile. Profiles Drug Subst Excip Relat Methodol. 32:67–96. 2005. View Article : Google Scholar : PubMed/NCBI
13	Liu J, Chen X, Ward T, Pegram M and Shen K: Combined niclosamide with cisplatin inhibits epithelial-mesenchymal transition and tumor growth in cisplatin-resistant triple-negative breast cancer. Tumour Biol. 37:9825–9835. 2016. View Article : Google Scholar : PubMed/NCBI
14	Liu J, Chen X, Ward T, Mao Y, Bockhorn J, Liu X, Wang G, Pegram M and Shen K: Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer. Int J Biochem Cell Biol. 71:12–23. 2016. View Article : Google Scholar : PubMed/NCBI
15	Taliaferro-Smith L, Oberlick E, Liu T, McGlothen T, Alcaide T, Tobin R, Donnelly S, Commander R, Kline E, Nagaraju GP, et al: FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells. Oncotarget. 6:4757–4772. 2015. View Article : Google Scholar : PubMed/NCBI
16	Schieber MS and Chandel NS: ROS links glucose metabolism to breast cancer stem cell and EMT phenotype. Cancer Cell. 23:265–267. 2013. View Article : Google Scholar : PubMed/NCBI
17	Lu L, Dong J, Wang L, Xia Q, Zhang D, Kim H, Yin T, Fan S and Shen Q: Activation of STAT3 and Bcl-2 and reduction of reactive oxygen species (ROS) promote radioresistance in breast cancer and overcome of radioresistance with niclosamide. Oncogene. 37:5292–5304. 2018. View Article : Google Scholar : PubMed/NCBI
18	Zhu Y, Zuo W, Chen L, Bian S, Jing J, Gan C, Wu X, Liu H, Su X, Hu W, et al: Repurposing of the anti-helminthic drug niclosamide to treat melanoma and pulmonary metastasis via the STAT3 signaling pathway. Biochem Pharmacol. 169:1136102019. View Article : Google Scholar : PubMed/NCBI
19	Osada T, Chen M, Yang XY, Spasojevic I, Vandeusen JB, Hsu D, Clary BM, Clay TM, Chen W, Morse MA, et al: Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations. Cancer Res. 71:4172–4182. 2011. View Article : Google Scholar : PubMed/NCBI
20	Londoño-Joshi AI, Arend RC, Aristizabal L, Lu W, Samant RS, Metge BJ, Hidalgo B, Grizzle WE, Conner M, Forero-Torres A, et al: Effect of niclosamide on basal-like breast cancers. Mol Cancer Ther. 13:800–811. 2014. View Article : Google Scholar
21	You S, Li R, Park D, Xie M, Sica GL, Cao Y, Xiao ZQ and Deng X: Disruption of STAT3 by niclosamide reverses radioresistance of human lung cancer. Mol Cancer Ther. 13:606–616. 2014. View Article : Google Scholar : PubMed/NCBI
22	Luo F, Luo M, Rong QX, Zhang H, Chen Z, Wang F, Zhao HY and Fu LW: Niclosamide, an antihelmintic drug, enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer. J Immunother Cancer. 7:2452019. View Article : Google Scholar : PubMed/NCBI
23	Schmalhofer O, Brabletz S and Brabletz T: E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev. 28:151–166. 2009. View Article : Google Scholar : PubMed/NCBI
24	Wu Q, Li J, Zhu S, Wu J, Chen C, Liu Q, Wei W, Zhang Y and Sun S: Breast cancer subtypes predict the preferential site of distant metastases: A SEER based study. Oncotarget. 8:27990–27996. 2017. View Article : Google Scholar : PubMed/NCBI
25	Fillmore CM and Kuperwasser C: Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 10:R252008. View Article : Google Scholar : PubMed/NCBI
26	Grimshaw MJ, Cooper L, Papazisis K, Coleman JA, Bohnenkamp HR, Chiapero-Stanke L, Taylor-Papadimitriou J and Burchell JM: Mammosphere culture of metastatic breast cancer cells enriches for tumorigenic breast cancer cells. Breast Cancer Res. 10:R522008. View Article : Google Scholar : PubMed/NCBI
27	Levine AJ and Puzio-Kuter AM: The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science. 330:1340–1344. 2010. View Article : Google Scholar : PubMed/NCBI
28	Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
29	Alasadi A, Chen M, Swapna GVT, Tao H, Guo J, Collantes J, Fadhil N, Montelione GT and Jin S: Effect of mitochondrial uncouplers niclosamide ethanolamine (NEN) and oxyclozanide on hepatic metastasis of colon cancer. Cell Death Dis. 9:2152018. View Article : Google Scholar : PubMed/NCBI
30	Lu J, Tan M and Cai Q: The Warburg effect in tumor progression: Mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Lett. 356 (2 Pt A):156–164. 2015. View Article : Google Scholar : PubMed/NCBI
31	Park SJ, Shin JH, Kang H, Hwang JJ and Cho DH: Niclosamide induces mitochondria fragmentation and promotes both apoptotic and autophagic cell death. BMB Rep. 44:517–522. 2011. View Article : Google Scholar : PubMed/NCBI
32	Khanim FL, Merrick BA, Giles HV, Jankute M, Jackson JB, Giles LJ, Birtwistle J, Bunce CM and Drayson MT: Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production. Blood Cancer J. 1:e392011. View Article : Google Scholar : PubMed/NCBI
33	Yu K, Wang T, Li Y, Wang C, Wang X, Zhang M, Xie Y, Li S, An Z and Ye T: Niclosamide induces apoptosis through mitochondrial intrinsic pathway and inhibits migration and invasion in human thyroid cancer in vitro. Biomed Pharmacother. 92:403–411. 2017. View Article : Google Scholar : PubMed/NCBI
34	Ye T, Xiong Y, Yan Y, Xia Y, Song X, Liu L, Li D, Wang N, Zhang L, Zhu Y, et al: The anthelmintic drug niclosamide induces apoptosis, impairs metastasis and reduces immunosuppressive cells in breast cancer model. PLoS One. 9:e858872014. View Article : Google Scholar : PubMed/NCBI
35	Yu H, Lee H, Herrmann A, Buettner R and Jove R: Revisiting STAT3 signalling in cancer: New and unexpected biological functions. Nat Rev Cancer. 14:736–746. 2014. View Article : Google Scholar : PubMed/NCBI
36	Duru N, Candas D, Jiang G and Li JJ: Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society. J Cancer Res Clin Oncol. 140:1–14. 2014. View Article : Google Scholar : PubMed/NCBI
37	Duru N, Fan M, Candas D, Menaa C, Liu HC, Nantajit D, Wen Y, Xiao K, Eldridge A, Chromy BA, et al: HER2-associated radioresistance of breast cancer stem cells isolated from HER2-negative breast cancer cells. Clin Cancer Res. 18:6634–6647. 2012. View Article : Google Scholar : PubMed/NCBI
38	Kim JS, Kim HA, Seong MK, Seol H, Oh JS, Kim EK, Chang JW, Hwang SG and Noh WC: STAT3-survivin signaling mediates a poor response to radiotherapy in HER2-positive breast cancers. Oncotarget. 7:7055–7065. 2016. View Article : Google Scholar : PubMed/NCBI
39	Chung SS, Giehl N, Wu Y and Vadgama JV: STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits. Int J Oncol. 44:403–411. 2014. View Article : Google Scholar : PubMed/NCBI
40	Li G, Zhao L, Li W, Fan K, Qian W, Hou S, Wang H, Dai J, Wei H and Guo Y: Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression. Oncotarget. 5:8317–8329. 2014. View Article : Google Scholar : PubMed/NCBI
41	Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, et al: Function of mitochondrial Stat3 in cellular respiration. Science. 323:793–797. 2009. View Article : Google Scholar : PubMed/NCBI
42	Yang R and Rincon M: Mitochondrial Stat3, the Need for Design Thinking. Int J Biol Sci. 12:532–544. 2016. View Article : Google Scholar : PubMed/NCBI
43	Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC and Levy DE: Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science. 324:1713–1716. 2009. View Article : Google Scholar : PubMed/NCBI
44	Ren X, Duan L, He Q, Zhang Z, Zhou Y, Wu D, Pan J, Pei D and Ding K: Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway. ACS Med Chem Lett. 1:454–459. 2010. View Article : Google Scholar : PubMed/NCBI
45	Chen H, Yang Z, Ding C, Chu L, Zhang Y, Terry K, Liu H, Shen Q and Zhou J: Discovery of O-Alkylamino Tethered Niclosamide Derivatives as Potent and Orally Bioavailable Anticancer Agents. ACS Med Chem Lett. 4:180–185. 2013. View Article : Google Scholar : PubMed/NCBI
46	Wu PF, Lin CH, Kuo CH, Chen WW, Yeh DC, Liao HW, Huang SM, Cheng AL and Lu YS: A pilot study of bevacizumab combined with etoposide and cisplatin in breast cancer patients with leptomeningeal carcinomatosis. BMC Cancer. 15:2992015. View Article : Google Scholar : PubMed/NCBI
47	Zhou L, Xu S, Yin W, Lin Y, Du Y, Jiang Y, Wang Y, Zhang J, Wu Z and Lu J: Weekly paclitaxel and cisplatin as neoadjuvant chemotherapy with locally advanced breast cancer: A prospective, single arm, phase II study. Oncotarget. 8:79305–79314. 2017. View Article : Google Scholar : PubMed/NCBI
48	Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, Rugo HS, Liu MC, Stearns V, Come SE, et al: TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer. J Clin Oncol. 33:1902–1909. 2015. View Article : Google Scholar : PubMed/NCBI
49	Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, Juul N, Leong CO, Calogrias D, Buraimoh A, et al: Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol. 28:1145–1153. 2010. View Article : Google Scholar : PubMed/NCBI
50	Shah N, Mohammad AS, Saralkar P, Sprowls SA, Vickers SD, John D, Tallman RM, Lucke-Wold BP, Jarrell KE, Pinti M, et al: Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases. Pharmacol Res. 132:47–68. 2018. View Article : Google Scholar : PubMed/NCBI